Induction by degraded carrageenan of colorectal tumors in rats.
Degraded carrageenan derived from the red seaweed Eucheuma spinosum was given to Sprague-Dawley rats through the diet, in drinking water or by stomach tube for up to 24 months. Carrageenan-induced squamous cell carcinomas, adenocarcinomas and adenomas in the colorectum were observed. Some rats had metastases to the regional lymph nodes of squamous cell carcinomas. These results show that degraded carrageenan is carcinogenic to the colorectum of the rat.


Supporting patients with healed leg ulcers.
There are high financial costs associated with recurrence of venous leg ulcers. Costs can be reduced and quality of life improved by a structured programme of education. Continued contact and support for patients following healing is beneficial for both patients and staff.


Amblyopia.
Amblyopia, commonly known as "lazy eye," is a frequent but preventable cause of decreased vision. An anatomically normal eye, free from organic disease, has reduced vision compared with the other eye. Ptosis of the eyelids, strabismus, certain refractive disorders and other abnormalities may precede amblyopia. If discovered early enough, usually before the age of five, amblyopia can often be reversed.


Real-time three-dimensional ultrasound - a valuable new tool in preoperative assessment of complex congenital cardiac disease.
Evaluating complex cardiac defects in small children preoperatively requires multiple diagnostic procedures including echocardiography, and also invasive methods such as cardiac catheterisation, computer-tomography and magnetic resonance imaging. We assessed the complex anatomy of the atrioventricular valves in atrioventricular septal defect using bedside real-time three-dimensional echocardiography and comparing these results to the anatomic findings at the time of operative intervention.


A new host-vector system allowing selection for foreign DNA inserts in bacteriophage lambda gtWES.
An improved vector (lambda gtWES.T5-622) for EcoRI fragments has been derived from EK2 vector lambda gtWES.lambdaB' by replacing the lambda B fragment with two identical 1.1 Md fragments from the pre-early region of bacteriophage T5. The new vector has two advantages which facilitate elimination of parental-type recombinants in an in vitro recombination experiment. Firstly, the 1.1 Md insert is too small to be re-inserted into lambda gtWES in a single copy. Secondly the 1.1 Md T5 fragment carries T5 gene A3 which prevents growth of phage retaining this fragment when the Excherichia coli host carries plasmid ColIb. Thus, essentially all plaques are due to phage with donor DNA inserts and are free of T5 DNA fragments. The size usually given as the theoretical minimum size for insertion into the lambda gt series of vectors is 0.66 Md. We have shown that this size is an underestimate and that the lower limit is about 1.6 Md. A precise estimate is difficult since there is strong selection, among phage having small inserts, for those which have acquired additional genetic material by duplication of the lambda DNA.


Bottom-up approaches for preparing drug nanocrystals: formulations and factors affecting particle size.
The solubility dependent bioavailability problem has become a major hurdle in drug development processes. Drug nanocrystals have been widely accepted by the pharmaceutical industry to improve the bioavailability of poorly water-soluble compounds. Top-down and bottom-up technologies are the two primary technical approaches of drug nanocrystal production. Though the top-down approach has been hugely successful on the commercial front, it has some inherent drawbacks that necessitate the emergence of alternate approaches. The bottom-up approach has not yet been established as a successful commercial technology. However, it has the potential to produce small size drug nanocrystals with less energy demanding processes. The bottom-up approach is commonly known as precipitation technique. It would be possible to stabilize particles at an early stage of precipitation and to generate drug nanocrystals. In the first part of this review article, we have discussed various bottom-up technologies that are currently in use. This has been followed by description and analysis of various process parameters that can affect the final particle size of the drug nanocrystals.


[Approach to the diagnosis of patients with febrile rash].
The patient with febrile rash poses a real diagnostic challenge to primary care physician. We report an original case of febrile macular rash whose etiology was related to sepsis secondary to pelviperitonitis and acute cholecystitis. Patient's history, careful physical examination, paraclinical examinations and favorable outcome allowed to retain the infectious origin of the rash, without microbiological confirmation in our study. The skin is an excellent marker for infection. Cutaneous manifestations are the most common signs observed in patients with sepsis at an early stage. Exanthema is the most common lesion; it is due to systemic effects of a microorganism infecting the skin. If there are no clinical signs of infection, early diagnosis can prevent complications.


Pharmacological effects and mechanism of Kaihoujian Throat Spray (children's type) in the treatment of pediatric acute pharyngitis and tonsillitis.
Kaihoujian Throat Spray children's type (KHJSC) is a Chinese medicine prescription for treating pediatric acute pharyngitis and tonsillitis (APT). However, its relevant mechanisms remain unclear. To investigate the pharmacological effects of KHJSC on APT in vitro and in vivo, and explore the possible mechanism and target proteins. The antiviral and antibacterial effects in vitro were evaluated by IC50 and MICs. Thirty-six Japanese white rabbits were averagely divided into control group, model group, amoxicillin group and 3 dose groups of KHJSC (720, 540 and 360 μL/kg/d). The model rabbits were injected with β-hemolytic Streptococcus solution into the tonsils for 2 consecutive days. KHJSC treatment started on the third day. The whole blood, serum, tonsil tissues and pharyngeal mucosa tissues were collected for routine blood tests, proteomic, ELISA and other tests on the sixth day. The IC50 of KHJSC on HCoV-229E, influenza PR8 and Ad3 were 1.99, 1.99 and 4.49 mg/mL, respectively; MICs of MDR-PA, MRSA and β-hemolytic Streptococcus were 350, 350, and 175 mg/mL. KHJSC markedly decreased the number of white blood cells, lymphocytes, neutrophils, and the level of IL-1β, IL-5, IL-6, IL-18, TNF-α and MCP-1; increased the content of IL-2 and IFN-γ. Proteomic analysis and ELISA revealed that PI3K-Akt signaling pathway, NF-κB signaling pathway and Toll-like receptor signaling pathway were the potential mechanisms of KHJSC against APT. These results provided the reference and scientific basis for the application of KHJSC in clinic and further mechanisms study.


Interleukin-9 produced by helper T cells stimulates interleukin-8 expression in endometriosis.
Inflammation and immune responses play crucial roles in the development of endometriosis. Although interleukin-9 (IL-9) has a pro-inflammatory function in chronic inflammatory diseases, its function in endometriosis remains unknown. Here, we aimed to investigate the significance of IL-9 and IL-9-producing lymphocytes in endometriosis. Specimens were obtained from patients with and without endometriosis. Peritoneal fluid (PF), peripheral blood (PB), and ovarian endometrioma (OE) tissues were analyzed for the proportion of CD4+ IL-9+ lymphocytes and IL-9 concentration using flow cytometry and enzyme-linked immunosorbent assay. OE, endometrium with endometriosis (EE), and normal endometrium (NE) were analyzed for IL-9 receptor (IL-9R) expression using immunohistochemical staining. IL-9-dependent changes in Interleukin-8 (IL-8) expression in endometrial stromal cells from OE (OESCs) were evaluated using real-time PCR. The proportion of CD4+ IL-9+ lymphocytes was higher in the PF, but not the PB, of patients with endometriosis than individuals without endometriosis (p < .05). However, IL-9 levels in the PF did not differ between those with and without endometriosis. We detected CD4+ IL-9+ lymphocytes in OE tissues and IL-9R in OE tissues and OESCs. In OESC culture, IL-9 significantly elevated IL-8 expression in a dose-dependent manner (p < .05), which was nullified by the addition of the anti-IL-9 receptor antibody. Furthermore, IL-9 additively stimulated IL-8 expression in the presence of TNF-α (p < .05). Our findings show that IL-9 produced by helper T cells induces IL-8 expression, suggesting that IL-9 plays an important role in the development of endometriosis by stimulating IL-8 expression.


Design and discovery of new 1,2,4-triazolo[4,3-c]quinazolines as potential DNA intercalators and topoisomerase II inhibitors.
A new series of 1,2,4-triazolo[4,3-c]quinazoline derivatives was designed and synthesized as Topo II inhibitors and DNA intercalators. The cytotoxic effect of the new members was evaluated in vitro against a group of cancer cell lines including HCT-116, HepG-2, and MCF-7. Compounds 14c , 14d , 14e , 14e , 15b , 18b , 18c , and 19b exhibited the highest activities with IC50 values ranging from 5.22 to 24.24 µM. Furthermore, Topo II inhibitory activities and DNA intercalating affinities of the most promising candidates were evaluated as a possible mechanism for the antiproliferative effect. The results of the Topo II inhibition and DNA binding tests were coherent with that of in vitro cytotoxicity. Additionally, the most promising compound 18c was analyzed in HepG-2 cells for its apoptotic effect and cell cycle arrest. It was found that 18c can induce apoptosis and arrest the cell cycle at the G2-M phase. Finally, molecular docking studies were carried out for the designed compounds against the crystal structure of the DNA-Topo II complex as a potential target to explore their binding modes. On the basis of these studies, it was hypothesized that the DNA binding and/or Topo II inhibition would participate in the noted cytotoxicity of the synthesized compounds.


Adaptation to sustained nitrogen starvation by Escherichia coli requires the eukaryote-like serine/threonine kinase YeaG.
The Escherichia coli eukaryote-like serine/threonine kinase, encoded by yeaG, is expressed in response to diverse stresses, including nitrogen (N) starvation. A role for yeaG in bacterial stress response is unknown. Here we reveal for the first time that wild-type E. coli displays metabolic heterogeneity following sustained periods of N starvation, with the metabolically active population displaying compromised viability. In contrast, such heterogeneity in metabolic activity is not observed in an E. coli ∆yeaG mutant, which continues to exist as a single and metabolically active population and thus displays an overall compromised ability to survive sustained periods of N starvation. The mechanism by which yeaG acts, involves the transcriptional repression of two toxin/antitoxin modules, mqsR/mqsA and dinJ/yafQ. This, consequently, has a positive effect on the expression of rpoS, the master regulator of the general bacterial stress response. Overall, results indicate that yeaG is required to fully execute the rpoS-dependent gene expression program to allow E. coli to adapt to sustained N starvation and unravels a novel facet to the regulatory basis that underpins adaptive response to N stress.


NFATc1 Expression as a Prognosticator in Urothelial Carcinoma of the Upper Urinary Tract.
We recently found that NFATc1, a member of the NFAT family and a key regulator of the immune response, could induce bladder carcinogenesis and cancer progression. In this study, we immunohistochemically stained for NFATc1 in upper urinary tract urothelial carcinoma (UUTUC) specimens and paired nonneoplastic urothelial tissues. NFATc1 was positive in 51 [52%; 40 (40%) weak (1+), 9 (9%) moderate (2+), and 2 (2%) strong (3+)] of 99 UUTUCs, which was significantly higher than in benign urothelium [30 (36%) of 83; 28 (34%) weak and 2 (2%) moderate] (0 vs 1+/2+/3+, P=.038; 0/1+ vs 2+/3+, P=.023). There were no significant associations between NFATc1 expression pattern and tumor grade or pT stage. However, the positive rates of NFATc1 expression tended to be higher in renal pelvic tumors (60%) than in ureteral tumors (42%; P=.080) as well as in pN+ tumors (75%) than in pN0 tumors (49%; P=.089). Kaplan-Meier and log-rank tests revealed that moderate (2+) to strong (3+) NFATc1 expression correlated with lower progression-free survival (P=.032) and cancer-specific survival (P=.005) rates in the 99 cases. Patients with high (2+/3+) NFATc1 muscle-invasive tumor (n=9) also had a significantly higher risk of cancer-specific mortality (P=.021) compared to those with low (0/1+) NFATc1 muscle-invasive tumor (n=53). Thus, compared with nonneoplastic urothelium, a significant increase in the expression of NFATc1 in UUTUC was seen, implying the involvement of NFATc1 signals in the development of UUTUC. The current results further suggest that NFATc1 overexpression serves as a predictor of poor prognosis in patients with UUTUC.


Perceived social support moderates the association between household dysfunction adverse childhood experiences (ACEs) and self-reported drug use among men who have sex with men in Los Angeles, California.
Adverse childhood experiences (ACEs) have been shown to be associated with drug use in adulthood. The single ACE of household substance use history (part of the household dysfunction category) has frequently been associated with drug use. Resilience factors such as perceived social support appear to buffer the association between ACEs and drug use and may be particularly relevant for urban men who have sex with men (MSM). The current study of low-income mostly Black and Latino MSM aims to investigate whether the cumulative ACE score predicts self-reported drug use in a dose-response manner and whether this potential association differs by perceived social support. Data was utilized from a longitudinal study of MSM (mean age=34; SD=7.1) with varied substance use behaviors (n = 321) collected between August 2014 and April 2022. Cumulative, household dysfunction ACEs, and the single ACE of household substance use history were investigated as predictors of self-reported drug use (methamphetamine, ecstasy, cocaine/crack, heroin/fentanyl, party drugs [GHB, special K, mushrooms, LSD/acid], other drugs [bath salts, PCP]) during the past six months in mixed-effects logistic regression models, with moderation analyses by perceived social support (measured by the Multidimensional Scale of Perceived Social Support) across all models using stratified analysis and one model of multiplicative interaction. There was no suggestion of a dose-response relationship between the number of ACEs and the predicted probability of self-reported drug use. Cumulative ACEs did not predict the outcome overall (aOR=1.99; 95% CI: 0.86-4.59), however, a positive association was estimated for individuals reporting lower levels of perceived social support (aOR=2.80; 95% CI: 0.97-8.06). The dimension of household dysfunction had a positive association with drug use (aOR=1.32; 95% CI: 1.00-1.74) whereas the dimension of childhood maltreatment did not. The association between household dysfunction and drug use was moderated by the perception of social support, with those reporting lower levels having greater odds of reporting drug use (aOR=2.94; 95% CI: 1.04-8.31). The association between household substance use history and self-reported drug use was similarly moderated by perceived social support in a multiplicative interaction model (p = .02). Perceived social support emerged as a potential buffering factor for any reported drug use, particularly for the single ACE of household substance use history. Given that the association between ACEs and drug use was weak among those with higher levels of perceived social support, promotion of social ties in the community may help reduce the burden of substance use among MSM exposed to ACEs.


Modulation of deoxycytidine kinase (dCK) and glycogen synthase kinase (GSK-3β) by anti-CD20 (rituximab) and 2-chlorodeoxyadenosine (2-CdA) in human lymphoid malignancies.
The combination of rituximab and 2-CdA is an effective therapy for B-cell tumors. However, the molecular mechanisms and enzymatic pathways involved in the interaction between the two agents are not fully understood. In this study, we provide molecular evidence for positive interaction between these two agents with resultant therapeutic benefit. Efficacy of the R-2CdA regimen was evaluated in thirteen patients with B-cell tumors (9 CLL; 3 WM and 1 FL), in vitro against 3 lymphoma cell lines and in a xenograft mouse model. Treatment-induced changes involving phenotype, kinase activity and protein expression were assessed in vitro and in the mouse xenograft tumors. The interaction between RTX and 2-CdA was analyzed using the multiple comparison method, Tukey's honestly significant difference (HSD). For the clinical and animal data, survival functions were estimated using the Kaplan-Meier method and compared by the log-rank test. P-values <0.05 were considered statistically significant. All statistical analyses were evaluated using GraphPad Prism 4 (San Diego, CA). 9 of 12 (75%) evaluable patients responded to the R-2-CdA regimen with median duration of response of 34 months. Median survival of patients from diagnosis and from completion of R-2-CdA treatment was 13.3 and 7.9 years, respectively. In vitro, the combination was effective in all 3 cell lines of lymphomas but with higher sensitivity in the follicular lymphoma cell line. The combination was also effective in the WSU-WM-SCID xenograft model with dose-dependent response and synergistic benefit. All animals were tumor-free for up to 120 days post 2 cycles of this regimen. Rituximab induced activation of deoxycytidine kinase (dCK), p38 mitogen activated protein kinase (p38MAPK) and glycogen synthase kinase-3β (GSK-3β) in the xenograft WSU-WM tumors. Chemical inhibition of p38MAPK led to inhibition of the GSK-3β phosphorylation suggesting that GSK-3β is regulated by p38MAPK in this model. Collectively, our studies show concordance between the activity of R-2-CdA in vitro, in human and in WSU-WM xenograft model attesting to the validity of this model in predicting clinical response. Modulation of dCK and GSK-3β by rituximab may contribute to the positive therapeutic interaction between rituximab and 2-CdA.


Monoclonal antibody analysis of diphtheria toxin--II. Inhibition of ADP-ribosyl-transferase activity.
Monoclonal antibodies directed against the enzymatically active A-fragment of diphtheria toxin were used to investigate further the structure-function relationships within fragment A. Of 16 such antibodies, all but two were directed against epitopes located within the carboxy-terminal 30-40 amino acids of fragment A. Interestingly, the antibodies recognize several epitopes in this small region and varied considerably in their effects on toxin functions. With regard to their effects on the enzymatic activity of fragment A, three types of antibodies were found: (1) antibodies which bind fragment A but fail to inhibit its ADP-ribosyltransferase activity, (2) antibodies which completely inhibit enzyme activity, and (3) antibodies which interact with fragment A to yield antigen-antibody complexes of diminished activity. The results are consistent with location of the catalytic center of fragment A within its carboxy-terminal ca 4000 dalton region.


Plasma levels of marine n-3 fatty acids and cardiovascular risk markers in renal transplant recipients.
Cardiovascular (CV) disease is the leading cause of death after renal transplantation. Marine n-3 polyunsaturated fatty acids (PUFAs) exert potential cardio-protective metabolic effects and might reduce CV morbidity and mortality in renal transplant recipients (RTRs). In this cross-sectional study of 1990 Norwegian RTRs, transplanted between 1999 and 2011, associations between plasma phospholipid marine n-3 PUFA levels and various CV risk markers at 10 weeks after transplant were evaluated. Higher plasma marine n-3 PUFA levels were associated with lower resting heart rate (rHR), lower fasting plasma glucose (fPG) levels, lower plasma triglyceride levels and higher plasma high-density lipoprotein (HDL) cholesterol levels. Plasma levels of eicosapentaenoic acid, but not docosahexaenoic acid, showed a positive association with plasma HDL cholesterol levels. Plasma marine n-3 PUFA levels were not associated with plasma low-density lipoprotein cholesterol levels, pulse wave velocity or systolic and diastolic blood pressure. A negative association between plasma marine n-3 PUFA levels and CV mortality was weakened by additional adjustment for plasma triglyceride levels and rHR. The ratio of n-6 to n-3 PUFAs showed similar associations with CV risk markers as absolute plasma marine n-3 PUFA levels. This is the first study in RTRs showing that marine n-3 PUFAs are negatively associated with rHR and fPG in addition to beneficial effects on plasma HDL cholesterol and triglyceride levels. Especially, effects on autonomic nervous function and triglyceride metabolism might contribute to explain the lower CV mortality risk with higher plasma marine n-3 PUFA levels previously shown in this cohort.


The impact of Australia's Royal Commission on child- and youth-serving organizations.
This commentary considers the impact to date of Australia's Royal Commission into Institutional Responses to Child Sexual Abuse on child- and youth-serving organizations, particularly its influence on organizations' efforts to create and maintain 'child safe, child friendly' cultures, policies and practices. Opportunities and challenges for organizational leaders are outlined. The commentary calls for more involvement by researchers in empirical research that is relevant to the causes and prevention of abuse in organizations, and for findings to be disseminated in ways that are useful to organizations.


Causes of women's postpartum depression symptoms: Men's and women's perceptions.
To describe men's and women's perceptions of the causes of women's PPD symptoms and to explore similarities and differences between men's and women's perceptions. Qualitative-descriptive study involving in-depth semi-structured individual interviews and content analysis. In-home interviews of participants recruited in two tertiary care hospitals, both in urban centres of the province of Quebec, Canada. Both members of 30 heterosexual couples from which women scored at least 12 on the Edinburgh Postnatal Depression Scale. Participants described nine causes underlying women's depressive symptoms: societal expectations and pressure on women, physical health problems, transition to parenthood, social connectedness, personality and past psychological history, child health and temperament challenges, unmet care needs, unmet expectations for childbirth, and other life stressors. With one exception, all causes were endorsed by both men and women. Only men mentioned societal pressure on women. Men and women mainly perceived similar causes, which could be explained by socio-cultural factors and extended paternal leaves. Understanding men's and women's perceptions could help tailoring health- care professionals' interventions to couples' needs.


Prevalence and factors associated with long-term remission in cutaneous lupus: A longitudinal cohort study of 141 cases.
Little is known about the prevalence and factors associated with long-term remission in cutaneous lupus erythematosus (CLE). To assess the prevalence, the factors associated with remission, and the long-term remission with and without treatment during CLE. Longitudinal cohort study including biopsy-proven patients with CLE seen between November 1, 2019 and April 30, 2021, with at least 6 months of follow-up after diagnosis. Demographic data, CLE subtypes, remission status, and treatments were recorded. Remission was defined by a Cutaneous Lupus Erythematosus Disease Area and Severity Index activity score of 0. Long-term remission was defined by remission >3 years. Among 141 patients included (81% of women), 93 (66%) were in remission at last follow-up with a median duration since diagnosis of 11.4 years (interquartile range, 4.2-24.7). Long-term remission was observed in 22 (19%) of 114 patients with at least 3 years of follow-up, including 5 (4.4%) with no systemic treatment. Active smoking (odds ratio, 0.22 [95%CI: 0.05-0.97]; P = .04) and discoid CLE lesions (odds ratio, 0.14 [95%CI, 0.04-0.48]; P = .004) were associated with a lower risk of long-term remission. Partial retrospective data collection and tertiary center population. Long-term remission is rare in CLE and negatively associated with active smoking and discoid CLE.


Safety and feasibility of same-day early discharge after endovascular revascularization of lower extremities in elderly. SENIOR-ER registry.
The aim of the study was to assess safety and feasibility of one-day early discharge (ODD) after endovascular revascularization (ER) of lower extremities in elderly. Safety and feasibility of ODD after ER have never been investigated in the elderly, despite the PAD rate has been rising in well-developed countries as their populations are getting older. The consecutive data of 477 patients after ER who were intended to ODD were reviewed. The ER procedure (balloon angioplasty, atherectomy, stenting) was performed due to significant, angiographically confirmed arterial stenosis with at least Rutheford III claudication. The population was divided into two groups: ≥70 years old (y. o.) in which were 235 patients and 220 patients <70 y. o., the younger control cohort. The follow-up was performed 24 hr after (24FU) the procedure and 30 days (30FU) after discharge. There were no differences between the groups in the ratio of same-day discharge (99% vs 99.5%, P = 0.6) and the mean time to ambulation was 287.4 ± 43.4 min versus 285.8 ± 45.7 min (P = 0.603). The ODD was not applied in 2 patients ≥70 y. o. due to two pseudoaneurysms requiring surgical repairs and in one from the control group due to retroperitoneal bleeding. There was no MACE or creatinine increase at 24 hr in both groups. At 30 days, there was no incidence of MACE in the ≥70 y. o. group while 3 MACE occurred in the control. The ratio of access site complications was comparable between the groups. The study allows for a hypothesis that the advantages of ODD could be safely extended to the patients ≥70 y. o.


Diversity and physiological properties of root endophytic actinobacteria in native herbaceous plants of Korea.
Endophytic actinobacterial diversity in the native herbaceous plant species of Korea was analyzed using a culture-based approach. Sixty one actinobacterial strains were isolated, and assigned to 15 genera based on 16S rRNA gene analysis. The members of the genus Streptomyces comprised 45.9% of the total isolates, followed by Micromonospora (18.8%), Rhodococcus (6.6%), Microbispora (4.9%), and Micrococcus (4.9%). Other minor constituents included members of Microbacterium, Streptacidiphilus, Arthrobacter, Dietzia, Kitasatospora, Herbiconiux, Mycobacterium, Nocardia, Rathayibacter, and Tsukamurella. Among the isolates, 65.6% exhibited at least one hydrolytic enzyme activity out of four, and 45.9% exhibited antagonistic activity against at least one fungal pathogen out of five, thus demonstrating that endophytic actinobacteria can be an important source of bioactive compounds. Notably, most strains of Streptomyces proved active for both enzymatic and antagonistic activities.


67 Ga-PSMA I&T for Radioguided Surgery of Lymph Node Metastases in Patients With Biochemical Recurrence of Prostate Cancer.
Radioguided lymph node dissection in patients with prostate cancer, and suffering from biochemical recurrence has been described thoroughly during the past few years. Several prostate-specific membrane antigen (PSMA)-directed ligands labeled with 111 In, 99m Tc, and 68 Ga have been published; however, limitations regarding availability, short half-life, high costs, and unfavorable high energy might restrict frequent use. This study aims at introducing 67 Ga as a promising radionuclide for radioguided surgery. Retrospective analysis was performed on 6 patients with 7 PSMA-positive lymph node metastases. 67 Ga-PSMA I&T (imaging and therapy) was synthesized in-house and intravenously applied according to §13 2b of the German Medicinal Products Act. Radioguided surgery was performed 24 hours after injection of 67 Ga-PSMA I&T using a gamma probe. Patient urine samples were collected. Occupational and waste dosimetry was performed to describe hazards arising from radiation. 67 Ga-PSMA application was tolerated without adverse effects. Five of 7 lymph nodes were detected on 22-hour SPECT/CT in 4 of 6 patients. During surgery, all 7 lymph node metastases were identified by positive gamma probe signal. Relevant accumulation of 67 Ga was observed in lymph node metastases (32.1 ± 15.1 kBq). Histology analysis of near-field lymph node dissection revealed more lymph node metastases than PET/CT (and gamma probe measurements) identified. Waste produced during inpatient stay required decay time of up to 11 days before reaching exemption limits according to German regulations. Radioguided surgery using 67 Ga-PSMA I&T is a safe and feasible option for patients suffering from biochemical recurrence of prostate cancer. 67 Ga-PSMA I&T was successfully synthesized according to Good Manufacturing Practice guidelines. Radioguided surgery with 67 Ga-PSMA I&T does not lead to relevant radiation burden to urology surgeons and represents a novel interdisciplinary approach in nuclear medicine and urology.


Ameliorative effects of silybin against avermectin-triggered carp spleen mitochondrial dysfunction and apoptosis through inhibition of PERK-ATF4-CHOP signaling pathway.
The aim of this study was to investigate the splenic tissue damage of environmental biological drug avermectin to freshwater cultured carp and to evaluate the effect of silybin on the splenic tissue damage of carp induced by avermectin. A total of 60 carp were divided into 4 groups with 15 carp in each group, including the control group fed with basic diet, experimental group fed with basal diet and exposed to avermectin (avermectin group), experimental group fed with basal diet supplement silybin (silybin group), and experimental group fed with basal diet supplement silybin and exposed to avermectin (silybin + avermectin group). The whole test period lasted for 30 days, and spleen tissue was collected for analysis. In this study, H&E staining, mitochondrial purification and membrane potential detection, ATP detection, DHE staining, biochemical tests, qPCR, immunohistochemistry, and apoptosis staining were used to evaluate the biological processes of spleen tissue injury, mitochondrial function, oxidative stress, apoptosis, and endoplasmic reticulum stress. The results show that silybin protected carp splenic tissue damage caused by chronic avermectin exposure, decreased mitochondrial membrane potential, decreased ATP content, ROS accumulation, oxidative stress, apoptosis, and endoplasmic reticulum stress. Silybin may ameliorate the splenic tissue damage of cultured freshwater carp caused by environmental biopesticide avermectin by alleviating mitochondrial dysfunction and inhibiting PERK-ATF4-CHOP-driven mitochondrial apoptosis. Adding silybin into the diet becomes a feasible strategy to resist the pollution of avermectin and provides a theoretical basis for creating a good living environment for freshwater carp.


Validation of the Ectasia Risk Score System for preoperative laser in situ keratomileusis screening.
To validate the Ectasia Risk Score System for identifying patients at high risk for developing ectasia after laser in situ keratomileusis (LASIK). Retrospective case-control study. Fifty eyes that developed ectasia and 50 control eyes with normal postoperative courses after LASIK were analyzed and compared using the previously described Ectasia Risk Score System, which assigns points in a weighted fashion to the following variables: topographic pattern, predicted residual stromal bed (RSB) thickness, age, preoperative corneal thickness (CT), and manifest refraction spherical equivalent (MRSE). In this series, 46 (92%) eyes with ectasia were correctly classified as being at high risk for the development of ectasia, while three (6%) controls were incorrectly classified as being at high risk for ectasia (P < 1 x 10(-10)). Significantly more eyes were classified as high risk by the ectasia risk score than by traditional screening parameters relying on abnormal topography or RSB thickness less than 250 micro (92% vs 50%; P < .00001). There was no difference in the sensitivity or specificity of the Ectasia Risk Score System in the population from which it was derived and this independent population of ectasia cases and controls. The Ectasia Risk Score System is a valid and effective method for detecting eyes at risk for ectasia after LASIK and represents a significant improvement over previously utilized screening strategies.


Introducing the clusterin gene into human renal cell carcinoma cells enhances their metastatic potential.
We recently reported a protective role of clusterin expression against apoptosis induced by a wide variety of stimuli in several human cancer models. In the current study we tested the hypothesis that clusterin over expression confers a benefit for the metastasis of renal cell carcinoma through the inhibition of apoptosis induced by the various obstacles the cancer cells may confront after detachment from their primary origin. We introduced clusterin complementary DNA into human renal cell carcinoma ACHN cells, which do not express detectable level of clusterin expression, and generated the clusterin over expressing cell line ACHN/CL and the control vector only transfected cell line ACHN/C. In vitro anti-cell death activity under anchorage independent conditions among ACHN sublines was examined by limiting dilution assay and cell survival assay in suspension. To investigate the in vivo effects of clusterin over expression on metastatic potentials each cell line was injected into the tail vein or renal subcapsule of nonobese diabetic, severe combined immunodeficient mice and the metastatic features in all abdominal and thoracic organs were evaluated. ACHN/CL showed significantly enhanced growth in limiting dilution cultures compared with ACHN/C. The analysis of cell survival in the floating assay also revealed that ACHN/CL had a powerful survival advantage in suspension compared with ACHN/C. Furthermore, ACHN/CL formed more than 5-fold as many metastatic nodules in the lung after intravenous injection than ACHN/C. Similarly more marked lung metastasis was observed after implanting ACHN/CL cells into the renal subcapsule than after implanting ACHN/C cells. In contrast, there were no significant differences among ACHN sublines in the growth rates in vitro and in vivo, cell motility or invasive ability. These findings suggest that, if clusterin is over expressed, it prolongs cell survival under unfavorable conditions in the metastatic process, resulting in the enhanced metastatic potential of renal cell carcinoma.


Female labor force participation and female mortality in Wisconsin 1974-1978.
The following research question is addressed in the study: what effect will the entrance of women into the labor force have on female mortality rates for all causes of death combined as well as specific causes relating to occupational stress, behavioral factors and physical hazards associated with occupation? This question is examined through comparisons of age, marital status and occupation-specific death rates for all causes of death combined and for selected causes of death. Death certificates provided by the Wisconsin Bureau of Health Statistics for the years 1974-1978 and population data provided by the 1976 Survey of Income and Education were used to construct death rates. The death rates of the white civilian female population of Wisconsin 16-64 years of age were examined using exploratory data analysis techniques (schematic plots and median polish) and standard errors. In general, the death rates of women in the labor force are substantially lower than those of housewives. These results may indicate that the role of housewife exposes women to health hazards. In addition, the results of this study may suggest some selectivity of healthy women into the labor force or a protective effect of labor force participation. In a limited number of instances, labor force participants' mortality rates exceed those of housewives. In the 60-64 year old population, white-collar workers, specifically, sales workers, managers and professionals, experience significantly higher death rates than housewives. In addition, specific groups of labor force participants experience significantly higher death rates than housewives for accidental deaths (i.e. laborers 16-44 and 45-54), deaths due to heart disease (i.e. laborers 45-54 and sales workers 60-64) and deaths due to malignant neoplasms (i.e. white-collar workers 60-64 years of age). The possibility that these instances indicate the direction of future mortality trends should be considered.


A protocol of systematic review and meta-analysis of continuous vacuum sealing drainage for diabetic foot ulcer.
Although continuous vacuum sealing drainage (CVSD) is often reported for the management of diabetic foot ulcer (DFU), its effectiveness has been evaluated primarily via clinical outcomes with limited attention. This study will aim to assess the effectiveness of CVSD for the treatment of patients with DFU. We will carry out a search in Cochrane Library, MEDLINE, Embase, CINAHL, PsycINFO, Web of Science, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure from their inceptions to the March 1, 2020. We will exert the searches in those electronic databases without restrictions of language, and the use of validated filters to obtain eligible studies. In addition to the search in electronic databases, we will retrieve studies from conference proceedings, and reference lists of included trials. We will use Cochrane risk of bias tool to assess study quality for each eligible study. All statistical analysis will be conducted using RevMan 5.3 software. This study will systematically summarize the most present evidence to assess the effectiveness and safety of CVSD for the management of DFU. The results from this study will contribute to obtain a genuine understanding of perspective from evidence-based medicine and a scientific basis for the effectiveness and safety of CVSD for the treatment of DFU. PROSPERO CRD42020170723.


Decreasing 203Hg retention by intraperitoneal treatment with monoalkyl esters of meso-2,3-dimercaptosuccinic acid in rats.
The effect of nine monoalkyl esters of meso-2,3-dimercaptosuccinic acid (DMSA) on 203Hg retention after a single i.p. dose was evaluated in 6-7 week-old female albino rats. The monoesters were the monomethyl (MMDMS), monoethyl (MEDMS), mono-n-propyl (Mn-PDMS), monoisopropyl (Mi-PDMS), mono-n-butyl (Mn-BDMS), monoisobutyl (Mi-BDMS), mono-n-amyl (Mn-ADMS), monoisoamyl (Mi-ADMS) and mono-n-hexyl (Mn-HDMS). Dimercaptosuccinic acid or one of the monoesters were administered at a dose of 0.25 mmol kg-1 body wt. twice, i.e. 30 min and 24 h after 203Hg administration. The whole body (WB) radioactivity was determined on the 2nd, 4th and 6th days. The radioactivity in the carcass (C) (whole body without the gastrointestinal tract), liver (L), both kidneys (K) and brain (B) was determined 6 days after 203Hg administration. All treated animals had a significantly lower body burden of mercury than the controls. The reduction of 203Hg retention in WB and other body compartments was higher in animals treated with monoesters than in rats treated with DMSA. The relative effectiveness of the monoesters was dependent on the nature of the alkyl groups, the efficiency being higher in higher analogues. Maximum activity was attained with the C5 (Mn-ADMS, Mi-ADMS) and C6 (Mn-HDMS) esters. These chelators reduced WB, C, L, K and B mercury retention by 90, 89, 76, 93 and 80%, respectively. Iso derivatives were more efficient than the normal isomers (Mi-PDMS > Mn-PDMS; Mi-BDMS > Mn-BDMS; Mi-ADMS > Mn-ADMS).(ABSTRACT TRUNCATED AT 250 WORDS)


Nitric oxide mitigates peroxide-induced iron-signaling, oxidative damage, and apoptosis in endothelial cells: role of proteasomal function?
In this mini-review, oxidant-induced transferrin receptor-mediated iron-signaling and apoptosis are described in endothelial and neuronal cells exposed to a variety of oxidative stresses. The role of nitric oxide and nitration in the regulation of iron homeostasis and oxidant-induced apoptosis is described. The interrelationship between oxidative stress, iron-signaling, and nitric oxide-dependent proteasomal function provides a rational mechanism that connects both oxidative and nitrative modifications.


Second messengers cAMP, Ca2+, and NO modulate functional properties of human lymphocytes under conditions of exposure to UV light.
We studied the effect of UV light (240-390 nm) in doses of 75.5-4530 J/m(2) on functional properties and level of intracellular messengers (cAMP, Ca(2+), NO) in lymphocytic cells of the peripheral blood. Correcting effects of UV light in a dose of 151 J/m(2) on cytotoxic activity of lymphocytes against Ehrlich ascetic carcinoma and calcium concentration in lymphocyte cytosol were observed. We found that UV light reduces the cAMP content and increases NO concentration (151-4530 J/m(2)) in photomodified cells. The involvement of adenylate cyclase and phosphoinositide signaling pathway into the mechanisms of modulation of functional properties of lymphocytes after exposure to UV light was demonstrated.


Indications for, and use of, cytotoxic agents in SLE.
Over the past decade, cytotoxic drugs have come to assume an increasingly important role in the management of systemic lupus erythematosus. Intravenous cyclophosphamide has become the standard treatment for lupus affecting major organs, in particular lupus nephritis. Cytotoxics with less potential for adverse side effects such as azathioprine and methotrexate are widely used in the management of non-major organ lupus and as an adjunct to reduce corticosteroid requirements. Recent clinical experience in lupus with newer cytotoxic drugs such as cyclosporin A, adenosine analogues, and mycophenolate mofetil appear promising and may offer improvements in lupus management in the future.


Randomized, controlled, bilateral (split-face) comparison trial of the tolerability and patient preference of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris.
Poor patient compliance is one of the main reasons for treatment failure in acne. Our objective was to evaluate the tolerability and patient preference of adapalene gel 0.1% compared with tretinoin microsphere gel 0.1% using a randomized, controlled, investigator-masked, bilateral (split-face), 4-week comparative study of the 2 products when applied once daily in 40 patients. We found that adapalene produced less stinging/burning than tretinoin at weeks 1 and 4 and, overall, more patients felt more skin irritation on the side of the face treated with tretinoin than on the side treated with adapalene (P<.05). At week 4, a significantly greater number of patients preferred adapalene gel 0.1% to tretinoin microsphere gel 0.1% (72.5% vs 27.5%, respectively, P<.01).


Tissue oxygen partial pressure distribution within the human skeletal muscle during hypercapnia.
In ten subjects CO2-inhalation elicited a significant increase in mean oxygen partial pressure within biceps muscle by more than 35%. Though mean oxygen partial pressure within biceps muscle increased, the distribution of oxygen partial pressure (pO2-histogram) did not change suggesting a physiological distribution of oxygen delivery within biceps muscle during hypercapnia. Buffering the blood pH did not abolish the effects of the CO2-inhalation. Therefore, a decrease of peripheral blood pH could not account for the hypercapnia induced increase of mean oxygen partial pressure within biceps muscle. Our data suggest that oxygen delivery to skeletal muscle was increased during hypercapnia, most probably due to a hypercapnia induced rise of mean capillary blood flow.


Mechanistic aspects of the oxidation of DNA constituents mediated by singlet molecular oxygen.
The present paper focussed on the mechanistic aspect of the reaction of singlet oxygen (1O2), in its lowest excited state (1 Delta g), toward DNA constituents. It is well known that 1O2 is able to react with the guanine moiety of DNA to produce almost specifically 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo). However, when 2'-deoxyguanosine (dGuo), free in solution, is the substrate, additional modified nucleosides are detected upon 1O2-mediated oxidation. The combined use of the thermolysis of a water-soluble naphthalene endoperoxide as a generator of 18O-singlet oxygen and the sensitivity of electrospray ionization-tandem mass spectrometry has allowed us to better understand the reactivity of 1O2 toward dGuo and 8-oxodGuo. As a striking observation, the secondary oxidation reaction of 8-oxodGuo, a main 1O2 oxidation product of dGuo, may explain, at least partly, the observed mutagenicity of 1O2.


Got Milk? Identifying and Characterizing Lactation Defects in Genetically-Engineered Mouse Models.
The ability to produce and expel milk is important for the health and survival of all mammals. Nevertheless, our understanding of the molecular events underlying the execution of this process remains incomplete. Whilst impaired mammary gland development and lactational competence remains the subject of focused investigations, defects in these events may also be an unintended consequence of genetic manipulation in rodent models. In this technical report, we outline established and emerging methods to characterize lactation phenotypes in genetically-engineered mouse models. We discuss important considerations of common models, optimized conditions for mating and the importance of litter size and standardization. Methods for quantifying milk production and quality, as well as protocols for wholemount preparation, immunohistochemistry and the preparation of RNA and protein lysates are provided. This review is intended to help guide researchers new to the field of mammary gland biology in the systematic analysis of lactation defects and in the preparation of samples for more focused mechanistic investigations.


Fungal Keratitis Caused by Talaromyces coalescens: A Case Report.
Fungal keratitis is a severe corneal infection, and the causative fungi include various rare fungal species. Fungal keratitis caused by Talaromyces species has yet to be reported, and there is no information about this fungus as a cause of keratitis. A 77-year-old man developed fungal keratitis while waiting for a donor cornea due to bullous keratopathy in his left eye. Fungal culture of a corneal scraping grew filamentous fungi, which were morphologically identified as Paecilomyces species. The corneal infection did not improve after topical administration of 1% voriconazole, and ribosomal DNA sequencing definitively verified the fungus to be Talaromyces coalescens. The lesion gradually improved after switching to topical 5% natamycin. Antifungal susceptibility tests determined the high minimum inhibitory concentrations of voriconazole to be > 8 μg/mL. This is the first report of Talaromyces fungal keratitis. Clinicians, especially those in ophthalmology, need to be aware of this rare fungus.


Increase of follicular helper T cells skewed toward a Th1 profile in CVID patients with non-infectious clinical complications.
Common variable immunodeficiency (CVID) is characterized by low levels of circulating immunoglobulins and defects in B cell maturation leading to an increased susceptibility to infections. Some patients develop complications such as autoimmune diseases, enteropathy, and lymphoproliferation, resulting in higher morbidity and mortality. Follicular helper T (Tfh) cells are specialized in helping B cell differentiation into Ig-producing cells. Three subsets have been described, namely non B-cell helper Tfh1 and the two B-helper cell subsets Tfh2 and Tfh17. We determined that circulating Tfh cells were elevated in CVID patients and skewed toward a Tfh1 profile. Interestingly, elevated levels of Tfh1 cells were significant only in patients harboring non-infectious complications regardless of the type of complication and inversely correlated with switched memory B cells. Moreover, CXCR3+ cells are increased in splenic CVID germinal centers. Our observations suggest that the altered balance in Tfh subsets in CVID is linked to a more severe disease.


The mobilization of aluminum from three brands of chewing gum.
The aluminium content of three chewing gums was measured before and after chewing. Analysis by atomic absorption spectrometry demonstrated that a single stick of chewing gum may contain as much as 4 mg aluminium. Analysis of samples after chewing revealed that between 2 and 21% of the aluminium in some chewing gums is mobilized during chewing. These data suggest that a stick of chewing gum can yield aluminium levels that correspond to 0.05-2.22% of the typical daily intake of aluminium from all dietary sources. Therefore, although the aluminium content of some chewing gums is relatively large, only a small proportion of the aluminium is mobilized by chewing. These gums are unlikely to contribute significantly to the daily intake of dietary aluminium.


Difference in injury pattern between drivers and front seat passengers involved in road traffic accidents in Scotland.
To investigate the frequency and pattern of injury in front seat passengers as compared with drivers, in Scotland. Using the Scottish Trauma Audit Group (STAG) database from 1994 to 2000, a search for injuries to eight anatomical body regions was performed. Injuries were identified and selected by their abbreviated injury score code. A comparison of injury frequency between drivers and front seat passengers was then made. There were 4189 drivers and 954 front seat passengers included in the study. Mortality was higher in the "front seat passengers" group (6.6% compared with 5.3% p = 0.13). Seven of the eight body regions selected showed higher rates of injury in front seat passengers. There were significantly more injuries to cervical spine (6.0% compared with 3.3% p<or=0.001), chest (41.4% compared with 29.0% p<or=0.001), and lumber spine (7.4% compared with 5.2% p<or=0.001) in front seat passengers. Front seat passengers are at increased risk of injury relative to drivers in actual road traffic accidents as recorded in the STAG database. This contradicts crash test data, which suggest drivers are less well protected than front seat passengers in laboratory conditions.


Femoral tibial bypass grafts. The alternative to amputation.
Severe ischemia and distal gangrene of lower extremities due to obstruction of the popliteal artery and its branches need not require major amputation. Autogenous vein grafts to the distal anterior tibial, posterior tibial, peroneal and dorsalis pedis arteries can avoid tissue loss in many instances.


Fatal BK polyoma viral pneumonia associated with immunosuppression.
BK polyoma virus has a worldwide distribution in the human population. Primary BK infection takes place during childhood, with the virus remaining latent in many sites. Immunosuppressive states can lead to viral reactivation associated with many clinical sequelae. We report a case of fatal BK-related pneumonia in a 69-year-old patient who was immunocompromised because of chemotherapy for chronic lymphocytic leukemia. Immunohistochemical, in situ hybridization, and polymerase chain reaction studies on paraffin-embedded lung tissue proved BK virus as the etiologic agent of pneumonia. The histological picture was remarkable for numerous intranuclear large basophilic viral inclusions with ground-glass appearance mainly in type II pneumocytes. Similar to many other infectious agents, BK virus is emerging as an important pathogen in immunocompromised patients, making it important to consider in the differential diagnosis.


Effects of tamoxifen and 4-hydroxytamoxifen on synchronized cultures of the human breast cancer cell line MCF-7.
The effect of antiestrogens on cultures of synchronized MCF-7 human breast cancer cells was studied. Cultures were synchronized by an eighteen hour block with 1.5 mM hydroxyurea. Tamoxifen or 4-hydroxytamoxifen was added at various times following removal of the hydroxyurea block and the cell number and rate of incorporation of 3H-thymidine by the cultures were followed for 48 hours through two waves of DNA synthesis. Antiestrogens added when hydroxyurea was removed inhibited only the second wave of DNA synthesis. Inhibition of the second wave only occurred if the antiestrogen was added before or at about the time of mitosis. To determine whether antiestrogen had to be present before mitosis in order to block the next round of DNA synthesis, cells in mitosis were selected by shaking them loose. The subsequent division of these cells was followed to determine the effect of treating them with antiestrogens before, after, or both before and after mitosis. The addition of antiestrogens at the time of mitosis proved sufficient to block the next round of cell division. Thus antiestrogens are cell cycle specific agents and appear to act at a point early in G1 to block the next round of DNA synthesis and cell division.


Prognostic Significance of Carcinoembryonic Antigen Staining in Cancer Tissues of Gastric Cancer Patients.
The aim of this study was to assess the significance of the correlation among tissue carcinoembryonic antigen (CEA) expression with serum CEA (sCEA) levels and long-term survival to highlight the clinical prognostic significance of tissue CEA expression in gastric cancer patients. Immunohistological method and radioimmunoassay were used to assess tissue and sCEA expression, respectively. Univariate and multivariate analyses were performed to determine correlations, and the Kaplan-Meier method was used to investigate the prognostic significance. Our results demonstrate that tissue CEA in gastric cancer is significantly correlated with preoperative sCEA levels (p = 0.031), depth of invasion (p = 0.001), lymph node metastasis (p < 0.001), distant metastasis (p = 0.001), and TNM staging (p < 0.001). The 5-year survival rates were 67.6, 53.9, and 40.1 % for negatively, moderately, and intensely positively stained tissues (p < 0.001), and 57.0 and 37.9 % for serum with normal and elevated CEA expression (p = 0.031). Multivariate analysis revealed that tissue CEA can be considered an independent prognostic factor. Further analysis illustrated that patients with negative expression in both tissue and serum had better prognosis compared with those positively expressing CEA in both tissue and serum and/or those positively expressing CEA in either tissue or serum (p < 0.001). Our results also demonstrated that patients with negative tissue CEA staining and elevated sCEA expression had a better 5-year survival. Tissue CEA expression in gastric cancer is directly correlated with sCEA levels and long-term prognosis. Thus, tissue CEA expression can be considered as a useful biomarker to improve the interpretation of sCEA levels in predicting long-term survival.


Visibility graph for time series prediction and image classification: a review.
The analysis of time series and images is significant across different fields due to their widespread applications. In the past few decades, many approaches have been developed, including data-driven artificial intelligence methods, mechanism-driven physical methods, and hybrid mechanism and data-driven models. Complex networks have been used to model numerous complex systems due to its characteristics, including time series prediction and image classification. In order to map time series and images into complex networks, many visibility graph algorithms have been developed, such as horizontal visibility graph, limited penetrable visibility graph, multiplex visibility graph, and image visibility graph. The family of visibility graph algorithms will construct different types of complex networks, including (un-) weighted, (un-) directed, and (single-) multi-layered networks, thereby focusing on different kinds of properties. Different types of visibility graph algorithms will be reviewed in this paper. Through exploring the topological structure and information in the network based on statistical physics, the property of time series and images can be discovered. In order to forecast (multivariate) time series, several variations of local random walk algorithms and different information fusion approaches are applied to measure the similarity between nodes in the network. Different forecasting frameworks are also proposed to consider the information in the time series based on the similarity. In order to classify the image, several machine learning models (such as support vector machine and linear discriminant) are used to classify images based on global features, local features, and multiplex features. Through various simulations on a variety of datasets, researchers have found that the visibility graph algorithm outperformed existing algorithms, both in time series prediction and image classification. Clearly, complex networks are closely connected with time series and images by visibility graph algorithms, rendering complex networks to be an important tool for understanding the characteristics of time series and images. Finally, we conclude in the last section with future outlooks for the visibility graph.


Pharmacology and Ethnomedicinal Potential of Selected Plants Species from Apiaceae (Umbelliferae).
The Apiaceae or Umbelliferae is one of the largest families in terms of species representation in the plant kingdom. It is also a prominent family in the field of phytochemicals and pharmacology. The family is also quite prominent in the production of spices and condiments and food supplements in nutrition, aside from the potential of species in the family to induce apoptotic, antimicrobial, antitumor, and hepatoprotective activities. This work presents a detailed structural elucidation and functional aspects of phytochemicals from the Apiaceae or Umbelliferae family. Furthermore, the application of members of this family in traditional and modern pharmacology is emphasized. This review also highlights the linkage of phytochemicals used in the conventional system of medication for the development of novel therapeutics through a chain of pre-clinical and clinical trials. This study may represent a valuable step ahead in the clinical development of natural drugs for curing several ailments, including respiratory and virus-related diseases.


Inhibition of superoxide dismutase, Vitamin C and glutathione on chemiluminescence produced by luminol and the mixture of sulfite and bisulfite.
In a system which consisted of luminol (3-aminophthalhydrazide), cobalt sulfate (CoSO4), alkaline buffer and the mixture of NaSO3 and sodium bisulfite (NaHSO3) (sulfite and bisulfite=3:1, m/m), a strong chemiluminescence (CL) was observed using a BPCL ultra-weak luminometer. The CL signals resulted from 3-aminophthalate (the product of oxidized luminol), and were affected by the buffer pH, buffer medium and the concentrations of luminol, CoSO4 and the NaSO3-NaHSO3 mixture. The observation that the CL intensities were inhibited by superoxide dismutase (SOD), Vitamin C (Vc) and glutathione (GSH) in a dose-dependent manner suggested that superoxide radical (O2*-) was involved in the CL reaction and responsible for oxidation of luminol.


[Obesity and radiation: technical difficulties, toxicity and efficacy].
The number of obese patients has increased in France over the last two decades, which has had an impact on the incidence of numerous types of cancer. The treatment of cancer by radiotherapy is impacted by obesity as a result of the physical, technical and dosimetric constraints, the acute and late toxicity, local control and the survival of patients.


Bi-stage control of dissolved oxygen to enhance cyclic adenosine monophosphate production by Arthrobacter A302.
Experiments confirmed dissolved oxygen (DO) definitely affects cyclic adenosine monophosphate (cAMP) production by Arthrobacter A302. Production of cAMP by batch fermentation was investigated under various DO conditions. A two-stage DO control strategy was proposed to achieve optimal production of cAMP based on the kinetic analysis: the DO level was controlled at 40% during the first 18 h and then switched to 30%. Relatively high cAMP production (9.9 g L(-1)) was achieved by applying this strategy. The cAMP productivity (0.14 g L(-1) h(-1)) was also successfully improved by 85.1, 59.3, 15.1 and 28.0%, compared to cases in which DO was uncontrolled or DO levels were held at 20, 30 and 40%, respectively. This is the first report of the use of a two-stage DO control strategy in cAMP production, and it was verified to be an effective method for enhancing the cAMP yield via this strain.


[High utilisers with affective and schizophrenic disorders in the psychiatric health care system: a comparison between Eastern and Western Germany].
High utilisers of psychiatric services are defined as a group of patients showing a great amount of service use, especially inpatient care, consequently causing immense costs. There is a lack of studies investigating differences between East and West Germany. Service use and psychopathology were examined in 350 high utilisers receiving inpatient treatment in one East German and three West German psychiatric hospitals. Whereas current length of stay was higher in participants from West Germany, readmissions were more frequent in the East German participants who also exhibited higher psychopathology. Presumably, the deficient situation of outpatient health care in East Germany is compensated by increased stationary admission, consequently leading to a structural promotion of high utilisation.


Energy filtered STEM imaging of thick biological sections.
Energy filtered imaging of thick biological specimens was analysed using a dedicated STEM fitted with an energy loss spectrometer and interfaced with a sophisticated data collection setup. All images were digital, thus permitting a quantitative analysis of the data. We also present a mathematical explanation of the data, which is useful in predicting the quality of thick specimen images formed with energy filtered electrons. It is known that increasing specimen thickness leads to a decrease of the zero energy loss intensity and an increase in higher (multiply scattered) energy loss electrons. We show that contrast decreases gradually with increased energy loss but, most important, the signal to noise ratio is maximal at an energy loss position slightly below the intensity maximum. This is the optimal position for imaging thick specimens. Moreover our studies confirm that the following parameters have similar effects on the energy loss spectra: (1) increased thickness (t); (2) higher average Z number elements (or lower mean free path); and (3) lower primary voltage (V0).


Alternative approaches to identify core bacteria in Fucus distichus microbiome and assess their distribution and host-specificity.
Identifying meaningful ecological associations between host and components of the microbiome is challenging. This is especially true for hosts such as marine macroalgae where the taxonomic composition of the microbiome is highly diverse and variable in space and time. Identifying core taxa is one way forward but there are many methods and thresholds in use. This study leverages a large dataset of microbial communities associated with the widespread brown macroalga, Fucus distichus, across sites and years on one island in British Columbia, Canada. We compare three different methodological approaches to identify core taxa at the amplicon sequence variant (ASV) level from this dataset: (1) frequency analysis of taxa on F. distichus performed over the whole dataset, (2) indicator species analysis (IndVal) over the whole dataset that identifies frequent taxa that are enriched on F. distichus in comparison to the local environment, and (3) a two-step IndVal method that identifies taxa that are consistently enriched on F. distichus across sites and time points. We then investigated a F. distichus time-series dataset to see if those core taxa are seasonally consistent on another remote island in British Columbia, Canada. We then evaluate host-specificity of the identified F. distichus core ASVs using comparative data from 32 other macroalgal species sampled at one of the sites. We show that a handful of core ASVs are consistently identified by both frequency analysis and IndVal approaches with alternative definitions, although no ASVs were always present on F. distichus and IndVal identified a diverse array of F. distichus indicator taxa across sites on Calvert Island in multiple years. Frequency analysis captured a broader suit of taxa, while IndVal was better at identifying host-specific microbes. Finally, two-step IndVal identified hundreds of indicator ASVs for particular sites/timepoints but only 12 that were indicators in a majority (> 6 out of 11) of sites/timepoints. Ten of these ASVs were also indicators on Quadra Island, 250 km away. Many F. distichus-core ASVs are generally found on multiple macroalgal species, while a few ASVs are highly specific to F. distichus. Different methodological approaches with variable set thresholds influence core identification, but a handful of core taxa are apparently identifiable as they are widespread and temporally associated with F. distichus and enriched in comparison to the environment. Moreover, we show that many of these core ASVs of F. distichus are found on multiple macroalgal hosts, indicating that most occupy a macroalgal generalist niche rather than forming highly specialized associations with F. distichus. Further studies should test whether macroalgal generalists or specialists are more likely to engage in biologically important exchanges with host.


Melanocortin-induced PKA activation inhibits AMPK activity via ERK-1/2 and LKB-1 in hypothalamic GT1-7 cells.
α-Melanocyte-stimulating hormone (α-MSH)-induced activation of the melanocortin-4 receptor in hypothalamic neurons increases energy expenditure and inhibits food intake. Active hypothalamic AMP-activated protein kinase (AMPK) has recently been reported to enhance food intake, and in vivo experiments suggested that intrahypothalamic injection of melanocortins decreased food intake due to the inhibition of AMPK activity. However, it is not clear whether α-MSH affects AMPK via direct intracellular signaling cascades or if the release of paracrine factors is involved. Here, we used a murine, hypothalamic cell line (GT1-7 cells) and monitored AMPK phosphorylation at Thr(172), which has been suggested to increase AMPK activity. We found that α-MSH dephosphorylated AMPK at Thr(172) and consequently decreased phosphorylation of the established AMPK substrate acetyl-coenzyme A-carboxylase at Ser(79). Inhibitory effects of α-MSH on AMPK were blocked by specific inhibitors of protein kinase A (PKA) or ERK-1/2, pointing to an important role of both kinases in this process. Because α-MSH-induced activation of ERK-1/2 was blunted by PKA inhibitors, we propose that ERK-1/2 serves as a link between PKA and AMPK in GT1-7 cells. Furthermore, down-regulation of liver kinase B-1, but not inhibition of calcium-calmodulin-dependent kinase kinase-β or TGFβ-activated kinase-1 decreased basal phosphorylation of AMPK and its dephosphorylation induced by α-MSH. Thus, we propose that α-MSH inhibits AMPK activity via a linear pathway, including PKA, ERK-1/2, and liver kinase B-1 in GT1-7 cells. Given the importance of the melanocortin system in the formation of adipositas, detailed knowledge about this pathway might help to develop drugs targeting obesity.


Highly chromophoric dual-terminus labeling of an intrinsically disordered native eukaryotic protein of interest at nanoscale.
Chemical conjugation of purified proteins of interest (POIs) in Escherichia coli cells is effective for high expression but has limitations for highly chromogenic dual labeling of intrinsically disordered native proteins (IDNPs). Our probes can tag IDNPs using chemical conjugation during protein synthesis and folding while preserving biologically active structures in mammalian cells. We fluorescently labeled IDNPs in mammalian cells using pure fluorescent methionine and ATTO 565-biotin at the N-or C-terminus, respectively. The dual-labeled Tat protein was used as a model for IDNPs in HeLa cells and detected using Ni-NTA beads to estimate its highly chromogenic concentration. We also demonstrated highly chromogenic double labeling of genetically encoded fluorescent-Tat expression in eukaryotic cells using a single fluorescent dye pair with Förster resonance energy transfer (FRET) ratio and two-color correlation analysis. This study aims to solve native POI processing and achieve ultra-sensitive protein folding for biological and ecological applications at the nanoscale.


Building on the backbone of CD47-based therapy in cancer: Combination strategies, mechanisms, and future perspectives.
Described as a "don't eat me" signal, CD47 becomes a vital immune checkpoint in cancer. Its interaction with signal regulatory protein alpha (SIRPα) prevents macrophage phagocytosis. In recent years, a growing body of evidences have unveiled that CD47-based combination therapy exhibits a superior anti-cancer effect. Latest clinical trials about CD47 have adopted the regimen of collaborating with other therapies or developing CD47-directed bispecific antibodies, indicating the combination strategy as a general trend of the future. In this review, clinical and preclinical cases about the current combination strategies targeting CD47 are collected, their underlying mechanisms of action are discussed, and ideas from future perspectives are shared.


Serosurvey for Nipah virus in bat population of southern part of India.
Nipah virus (NiV) is one of the priority pathogens with pandemic potential. Though the spread is far slower than SARS-CoV-2, case fatality is the biggest concern. Fruit bats belonging to genus Pteropus are identified to be the main reservoir of the virus causing sporadic cases and outbreaks in Malaysia, Bangladesh and India. The sudden emergence of Nipah in Kerala, India during 2018-2019 has been astonishing with respect to its introduction in the unaffected areas. With this, active Nipah virus surveillance was conducted among bat populations in Southern part of India viz., Karnataka, Kerala, Tamil Nadu, Telangana, Puducherry and Odisha during January-November 2019. Throat swabs/rectal swabs (n = 573) collected from Pteropus medius and Rousettus leschenaultii bat species and sera of Pteropus medius bats (n = 255) were screened to detect the presence of Nipah viral RNA and anti-Nipah IgG antibodies respectively. Of 255 P. medius bats sera samples, 51 bats (20%) captured from Karnataka, Kerala, Tamil Nadu and Puducherry demonstrated presence of anti-Nipah IgG antibodies. However, the presence of virus couldn't be detected in any of the bat specimens. The recent emergence of Nipah virus in Kerala in September 2021 warrants further surveillance of Nipah virus among bat populations from the affected and remaining states of India.


The added value of haemoglobin to height, age, and sex to predict DLCO in subjects with preserved exercise capacity.
The single breath diffusion capacity for carbon monoxide (DLCO) captures several aspects of the role of the lung in meeting the metabolic demands of the body. The magnitude of the independent contributors to the DLCO is unknown. The aim of this study was to investigate the factors that independently contribute to the DLCO. The objective was to investigate the impact of height, age, sex and haemoglobin on DLCO, alveolar volume (VA) and carbon monoxide transfer coefficient (KCO). Study participants were pre-screened based on normal exercise capacity achieved during an incremental cardio-pulmonary exercise testing (CPET) using cycle ergometry at McMaster University Medical Center between 1988-2012. Participants who had an FEV1>80% predicted, with an FEV1/FVC ≥0.7 and who achieved a maximum power output ≥80% were selected for analysis. In total, 16,298 subjects [61% male, mean height 1.70m (range 1.26-2.07), age 49 yrs (10-94), weight 79 kg (23-190) had DLCO measured while demonstrating normal spirometry and exercise capacity. The DLCO increased exponentially with height, was 15% greater in males, increased with age yearly until 20, then decreased yearly after the age of 35, and was 6% higher per gram of haemoglobin (5.58*Height(m)1.69*1.15 in Males*(1-0.006*Age>35)*(1+0.01*Age<20) *(1+0.06*Hb gm/dl), (r = 0.76). Height, age, sex, and haemoglobin all have independent influence on the DLCO in subjects with normal spirometry and preserved exercise capacity.


Hospital discharges-based search of acute flaccid paralysis cases 2007-2016 in Italy and comparison with the National Surveillance System for monitoring the risk of polio reintroduction.
Acute flaccid paralysis (AFP) surveillance has been adopted globally as a key strategy for monitoring the progress of the polio eradication initiative. Hereby, to evaluate the completeness of the ascertainment of AFP cases in Italy, a hospital-discharges based search was carried out. AFP cases occurring between 2007 and 2016 among children under 15 years of age were searched in the Italian Hospital Discharge Records (HDR) database using specific ICD-9-CM diagnostic codes. AFP cases identified between 2015 and 2016 were then compared with those notified to the National Surveillance System (NSS). Over a 10-year period, 4163 hospital discharges with diagnosis of AFP were reported in Italy. Among these, 956 (23.0%) were acute infective polyneuritis, 1803 (43.3%) myopathy, and 1408 (33.8%) encephalitis, myelitis and encephalomyelitis. During the study period, a decreasing trend was observed for all diagnoses and overall the annual incidence rate (IR) declined from 5.5 to 4.5 per 100,000 children. Comparing NSS with HDR data in 2015-2016, we found a remarkable underreporting, being AFP cases from NSS only 14% of those recorded in HDR. In particular, the acute infective polyneuritis cases reported to NSS accounted for 42.6% of those detected in HDR, while only 0.9% of myopathy cases and 13.1% of encephalitis/myelitis/encephalomyelitis cases have been notified to NSS. The highest AFP IRs per 100,000 children calculated on HDR data were identified in Liguria (17.4), Sicily (5.7), and Veneto (5.1) Regions; regarding the AFP notified to the NSS, 11 out of 21 Regions failed to reach the number of expected cases (based on 1/100,000 rate), and the highest discrepancies were observed in the Northern Regions. Overall, the national AFP rate was equal to 0.6, therefore did not reach the target value. AFP surveillance data are the final measure of a country's progress towards polio eradication. The historical data obtained by the HDR have been useful to assess the completeness of the notification data and to identify the Regions with a low AFP ascertainment rate in order to improve the national surveillance system.


Visual disability in selected acts of terror, warfare, and natural disasters of the last 25 years: a concise narrative review.
A review of ocular injury related to mass disaster over the past 25 years, including injury type, treatment, and final visual outcome. Retrospective review. Injury types, treatment, and final visual acuity. Acts of terror and war result in significant and increasingly more common ocular injury. Natural disasters were much less likely to cause lasting or permanent injury. Final visual acuity was rarely reported. Primary prevention is superior to treatment in acts of war and terror. Ocular injury is rarely reported by first response to natural disaster.


Postnatal MSG treatment attenuates angiotensin II (AII) induced drinking in rats.
Exogenous angiotensin II (AII) administration produces a robust drinking response, even in water-satiated rats. All receptors are located in the hypothalamus and circumventricular organs (CVOs). Early postnatal administration of monosodium glutamate (MSG) produces hypothalamic/CVO damage. Therefore MSG might damage hypothalamic/CVO neurons important for producing the drinking response to AII. Few noninvasive procedures or tests exist to indicate the presence of a MSG lesion. Thus, the present study sought to determine whether altered water consumption after AII administration would signify the presence of a MSG lesion, as well as to demonstrate hypothalamic/CVO involvement in AII-induced drinking. Adult rats (dosed as neonates with MSG or saline) were given various doses of AII and the beta-adrenergic agonist isoproterenol. MSG-treated rats drank significantly less water after 100 ug/kg, sc AII than control rats. MSG-treated rats also had an unexpectedly high mortality after 100 ug/kg, sc isoproterenol. Thus, measurement of the drinking response may be a sensitive, noninvasive method for detecting neurotoxic damage to hypothalamic/CVO sites critical for the central action of AII.


Malignant neoplasm in kidney transplantation.
The kidney recipient is at a higher risk for cancer than is the general population, although the incidence of neoplasms in general is considered lower in Japan than in Western countries. The cause of this increased risk associated with either transplantation or geography has not yet been established. The incidences and sites of malignant neoplasms were analyzed in 285 kidney recipients, who had been followed up for 3007 patient-years. The relationship between immunosuppressive states, the numbers of CD4-positive T lymphocytes, and the presence of malignant neoplasms was studied retrospectively. Eighteen malignant neoplasms were found in 17 of the 285 patients (6%). The malignancies developed in these patients an average of++ 1 26.5 months after transplantation. The incidence was only 3.9% at 10 years, increasing to 13.9% at 20 years. No difference in the time-course incidence was found between azathioprine-based and cyclosporin-based immunosuppressive regimens. The malignancies developed in the digestive organs in more than half of the patients, and were mainly in the liver, colon and rectum, and stomach, with a relatively low incidence of skin cancer and lymphoma. There was only one case of Epstein-Barr virus genome found in 5 specimens that were tested. Concerning the immunosuppressive state, CD4-positive T lymphocyte counts were not related directly with malignancies in our series. The cumulative incidence of malignancy increased markedly in the second posttransplant decade. The site of cancers in kidney recipients mirrors that of general Japanese malignancies. Our results revealed neither the cause nor predictor for malignancies in kidney transplant patients.


Differential modulation by vascular nitric oxide synthases of the ethanol-evoked hypotension and autonomic dysfunction in female rats.
We recently reported that chronic exposure to ethanol lowers blood pressure (BP) via altering cardiac contractility and autonomic control in female rats. In this investigation we conducted pharmacological and molecular studies to elucidate the role of constitutive and inducible nitric oxide synthase (NOS) in these hemodynamic effects of ethanol. Changes caused by selective inhibition of eNOS [N(5)-(1-iminoethyl)-l-ornithine; l-NIO], nNOS (N(ω)-propyl-l-arginine; NPLA), or iNOS (1400W) in BP, heart rate (HR), myocardial contractility index (dP/dt(max)), and power spectral indices of hemodynamic variability were evaluated in telemetered female rats receiving ethanol (5%, w/v) or control liquid diet for 8 weeks. Ethanol increased plasma nitrite/nitrate (NOx) and enhanced the phosphorylation of eNOS and nNOS, but not iNOS, in the tail artery. Ethanol also reduced BP, +dP/dt(max), low-frequency bands of interbeat intervals (IBI(LF), 0.25-0.75 Hz) and IBI(LF/HF) ratio while high-frequency bands (IBI(HF), 0.75-3 Hz) were increased, suggesting parasympathetic overactivity. l-NIO (20 mg/kg i.p.) caused greater increases in BP in control than in ethanol-fed rats but elicited similar reductions in IBI(LF/HF) and +dP/dt(max) both groups. NPLA (1 mg/kg i.p.) caused minimal effects in control rats but exacerbated the reductions in BP, +dP/dt(max), and IBI(LF/HF) in ethanol-fed rats. No hemodynamic modifications were caused by 1400W (5 mg/kg i.p.) in either rat group. Together, these findings suggest that nNOS acts tonically to offset the detrimental cardiovascular actions of ethanol in female rats, and the enhanced vascular NO bioavailability may explain the blunted l-NIO evoked pressor response in ethanol-fed rats.


Understanding the impact of the economic crisis on child health: the case of Spain.
The objectives of the study were to explore the effect of the economic crisis on child health using Spain as a case study, and to document and assess the policies implemented in response to the crisis in this context. Serial cross-sectional data from Eurostat, the Spanish Health Interview Survey, and the database of childhood hospitalisation were analysed to explore impacts on child health, and key determinants of child health. A content analysis of National data sources/government legislation, and Spanish literature was used to describe policies implemented following the crisis. Unemployment rates in the general population (8.7% in 2005 and 25.6% in 2013), and children living in unemployed families (5.6% and 13.8%) increased in the study period. The percentage of children living under the poverty line, and income inequalities increased 15-20% from 2005 to 2012. Severe material deprivation rate has worsened in families with Primary Education, while the number of families attending Non-Governmental Organisations has increased. An impact on children's health at the general population level has not currently been detected; however an impact on general health, mental health and use of healthcare services was found in vulnerable groups. Investment in social protection and public policy for children showed a reduction as part of austerity measures taken by the Spanish governments. Despite the impact on social determinants, a short-term impact on child health has been detected only in specific vulnerable groups. The findings suggest the need to urgently protect vulnerable groups of children from the impact of austerity.


Treatment of supratentorial high grade gliomas with split course high fractional dose postoperative radiotherapy.
Ninety-two patients with malignant supratentorial gliomas diagnosed from 1977 to 1983 received split course external beam radiotherapy. The initial course of radiation consisted of 3000 cGy whole brain in ten fractions 5 days a week. After a 2-week rest, treatment was continued to a portal restricted to the computerized tomography scan demonstrated abnormality plus a margin for an additional 2100 cGy (total 5100 cGy/17 fx/36 days). The optic chiasm and hypothalamus were excluded from the high dose region. Following review of all pathologic specimens, three patients with grade II glioma, three lacking histologic confirmation, two unbiopsied and eleven not receiving the prescribed treatment were excluded from the survival analysis. No patients were lost to follow-up. Surviving patients were followed 85 months (median); range 68-125 months. All remaining patients were followed until death. The median actuarial survival for 73 grade III and IV patients was 12.5 months. The 5-year actuarial survival was 10%. The median survival for 54 grade IV patients was 10 months. The 5-year survival was 4%. For 19 grade III patients the median survival was 22.5 months. The 5-year survival was 26%. There was one long-term grade IV survivor (68 mos.) and four long-term grade III survivors (76, 85, 108, 125 mos). No patient developed optic nerve or chiasm injury. One patient, an 85 months survivor, had biopsy documented radionecrosis and hemiparesis. The incidence of necrosis among 62 patients alive 6 months or more (and therefore at risk of brain necrosis) is 1/62 (2%). The incidence among survivors is 1/5. The nominal standard dose for this regimen is 1749 ret. The predictive value of the "nominal standard dose" and "equivalent dose" formulae for brain necrosis is explored. We conclude (a) that this regimen provides a survival probability equivalent to conventional treatment for grade III and IV supratentorial gliomas, (b) that neither the equivalent nor nominal standard doses predicted the incidence of brain necrosis, (c) that the time dose schedule is well tolerated and has an acceptable risk-benefit ratio, (d) that its advantage to the patient is decreased time requirement and cost.


[Cytogenetic analysis of the pronucleus after an interspecies man-hamster model of fertilization].
A cytogenetic analysis of seventy human sperms originating from seven normal subjects is described. Results are compared to those of previously reported studies. The share of male and female contributions in the genesis of chromosomal abnormalities in human zygotes is discussed.


Peripapillary RNFL thickness in nonexudative versus chronically treated exudative age-related macular degeneration.
To compare the peripapillary retinal nerve fibre layer (RNFL) thickness in nonexudative versus exudative age-related macular degeneration (wet AMD) eyes treated chronically with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). Cross-sectional study. Twenty-nine patients with unilateral wet AMD with at least 12 prior intravitreal anti-VEGF injections and 2 years of therapy were analyzed. The fellow eye with nonexudative (dry) AMD with no prior treatment served as the control group. All patients were prospectively enrolled from a single academic subspecialist practice. Bilateral spectral-domain optical coherence tomography (Cirrus SD-OCT; Carl Zeiss Meditec, Dublin, Calif.) of the peripapillary RNFL was performed on all pairs of eyes. Optic nerve head (ONH) parameters were also computed. The primary outcome was mean difference in peripapillary RNFL thickness compared between the treated and the nontreated eyes. Mean RNFL in the chronically treated eyes (95.0 [95% CI 89.8-100.2] μm) was significantly greater than the nontreated fellow eyes (89.9 [95% CI 85.5-94.3] μm) (p = 0.01). Quadrantic optic nerve analysis revealed the temporal RNFL to be greater in the treated group (p = 0.02), whereas all other locations were similar. No significant differences were found between the 2 groups in any ONH parameters. This study demonstrated no deleterious optic nerve RNFL thinning in a series of wet AMD eyes with long-term repetitive exposure to intravitreal anti-VEGF injections. Furthermore, we observed that those with wet AMD have a relatively thickened temporal peripapillary RNFL layer, which is an important association for all observers of optic nerve disease.


Angiogenesis in ovarian cancer: molecular pathology and therapeutic strategies.
Ovarian cancer claims the lives of more women in North America each year than all other gynecologic malignancies combined. Despite the high initial response rates of patients with advanced ovarian cancer to aggressive primary surgical debulking followed by combination chemotherapy, the majority of patients will ultimately develop disease recurrence. The high risk of relapse and nearly guaranteed incurability after relapse is due to genetic instability and a high mutation rate of neoplastic cells that together allow for a high risk of selection for drug resistance. Given the seemingly insurmountable obstacle that acquired drug resistance presents in a setting of minimal, often undetectable, residual tumor burden in women with ovarian cancer, antiangiogenic-targeted therapies offer an attractive strategy for enhanced long-term disease-free survival. The past decade has witnessed a substantial proliferation in our knowledge regarding tumor angiogenesis, which has spurred interest in antiangiogenesis drug development. Current clinical trials are evaluating these agents in a variety of solid tumors, including ovarian cancer. Preliminary work has provided hope that the addition of antiangiogenic therapies may be incorporated into the treatment of women afflicted with ovarian cancer and may translate into enhanced survival.


Searching for autoimmune encephalitis: Beware of normal CSF.
To determine the prevalence of cerebrospinal fluid (CSF) markers associated with inflammation (i.e., elevated white blood cell count, protein concentration, and CSF-specific oligoclonal bands) in patients with early active autoimmune encephalitis (AE). CSF characteristics, including WBC count, protein concentration, and oligoclonal banding, were analyzed in patients diagnosed with AE at two tertiary care centers. Ninety-five patients were included in the study. CSF white blood cell counts and protein levels were within normal limits for 27% (CI95%: 19-37) of patients with AE. When results of oligoclonal banding were added, 14% (CI95%: 6-16) of patients with AE had "normal" CSF. The median CSF white blood cell count was 8 cells/mm3 (range: 0-544) and the median CSF protein concentration was 0.42 g/L (range: 0.15-3.92). White blood cell counts and protein levels were within normal limits in the CSF of a substantial proportion of patients with early active AE. Inclusion of CSF oligoclonal banding identified a higher proportion of patients with an inflammatory CSF profile, especially when CSF was sampled early in the disease process.


Pediatric Medullary Stroke, Severe Dysphagia, and Multimodal Intervention.
Lateral medullary syndrome/Wallenberg syndrome is a stroke in the lateral medulla with symptoms often including dysphagia and dysphonia. In adults, this stroke is the most common brainstem stroke, but it is rare in the pediatric population. Insults to the medulla can involve the "swallowing centers," the nucleus ambiguus and nucleus tractus solitarius, and the cranial nerves involved in swallowing, namely IX (glossopharyngeal) and X (vagus). These individuals can develop severe dysphagia with an inability to trigger a swallow due to pharyngeal weakness and impaired mechanical opening of the upper esophageal sphincter (UES) which can result in aspiration. We present a 7-year-old male with 22q11.2 deletion syndrome (velocardiofacial syndrome) and velopharyngeal insufficiency who underwent pharyngeal flap surgery at an outside hospital whose post-operative course was complicated by adenovirus, viral myocarditis, and dorsal medullary stroke. He required a tracheostomy and gastrostomy tube. He was discharged from that hospital and readmitted to our hospital 4 months later for increased oxygen requirement, requiring a 5 month admission in the intensive care units. His initial VFSS revealed absent UES opening with the entire bolus remaining in the pyriform sinuses resulting in aspiration. His workup over the course of his admission included multiple videofluoroscopic swallow studies (VFSS), flexible endoscopic evaluation of swallowing (FEES), and pharyngeal and esophageal manometry. Intervention included intensive speech therapy, cricopharyngeal Botox® injection, and cricopharyngeal myotomy. Nineteen months after his stroke, he transitioned to oral intake of solids and liquids with adequate movement of the bolus through the pharynx and UES and no aspiration on his VFSS.


Expression of growth inhibitory factor (GIF) in normal and injured rat brains.
Immunohistochemical study on growth inhibitory factor (GIF) in rat brain has revealed that a glial cell layer on the surface of cerebral cortex and the cells surrounding Purkinje cells has been reported. In addition, neurons in gray matter were weakly immunostained for GIF. In situ hybridization using digoxigenin-labeled single-strand RNA probes also demonstrated that most of the neurons and small round cells, which were presumably astrocytes, expressed GIF mRNA in the cerebral cortex of rat brain. These findings indicate that GIF is produced in neurons as well as in astrocytes. The most prominent findings in this study are, a very strong reaction of GIF and GIF mRNA in the reactive astrocytes around the site of injury induced by stab wound or kainic acid injection. These results raised the possibility that GIF may act as an acute-phase protein in reactive astrocytes and have a role in tissue repair.


Determination of plasma ET-1 by RIA--risks and limitations.
Plasma concentrations of the vasoconstrictor peptide endothelin-1 (ET-1) were determined in nonobese healthy subjects as well as in unspecified patients using three different commercially available radioimmunoassays (RIAs) and the respective recommended prepurification procedures. Depending on the antibody and extraction procedure applied different ET-1 concentrations were measured in identical plasma samples. Thus, this study clearly documents that ET-1 concentrations measured in plasma samples represent apparent concentrations which have to be interpreted with caution.


Characterization and identification of differentially expressed microRNAs during the process of the peribiliary fibrosis induced by Clonorchis sinensis.
Clonorchis sinensis (C. sinensis) infection can lead to biliary fibrosis. MicroRNAs (miRNAs) play important roles in regulation of genes expression in the liver diseases. However, the differential expression of miRNAs that probably regulates the portal fibrogenesis caused by C. sinensis has not yet been investigated. Hepatic miRNAs expression profiles from C. sinensis-infected mice at different time-points were analyzed by miRNA microarray and validated by quantitative real-time PCR (qRT-PCR). 349 miRNAs were differentially expressed in the liver of the C. sinensis-infected mice at 2, 8 or 16weeks post infection (p.i.), compared with those at 0week p.i., and there were 143 down-regulated and 206 up-regulated miRNAs among them. These all dysregulated miRNAs were potentially involved in the pathological processes of clonorchiasis by regulation of cancer-related signaling pathway, TGF-β signaling pathway, MAPK signaling pathway, Toll-like receptor signaling pathway, PI3K /AKT signaling pathway, etc. 169 of these dysregulated miRNAs were predicted to be involved in the TGF/Smads signaling pathway which plays an important role in the biliary fibrosis caused by C. sinensis. Additionally, miRNA-32, miRNA-34a, miRNA-125b and miRNA-497 were negatively correlated with Smad7 expression, indicating these miRNAs may specifically down-regulate Smad7 expression and participate in regulation of biliary fibrosis caused by C. sinensis. The results of the present study for the first time demonstrated that miRNAs were differentially expressed in the liver of mice infected by C. sinensis, and these miRNAs may play important roles in regulation of peribiliary fibrosis caused by C. sinensis, which may provide possible therapeutic targets for clonorchiasis.


Serum levels of heat shock protein 27 in patients with acute ischemic stroke.
Expression of intracellular heat shock protein 27 (Hsp27) rises in the brain of animal models of cerebral ischemia and stroke. Hsp27 is also released into the circulation and the aim of the present study was to investigated if serum Hsp27 (sHsp27) levels are altered in patients with acute ischemic stroke. sHsp27 was measured in 15 patients with acute ischemic stroke and in 14 control subjects comparable for age, sex, and cardiovascular risk factors. In patients, measurements were performed at admission and 1, 2, and 30 days thereafter. At admission, mean sHsp27 values were threefold higher in patients than in controls. In patients, sHsp27 values dropped after 24 h, rose again at 48 h, and markedly declined at 30 days, indicating the presence of a temporal trend of sHsp27 values following acute ischemic stroke.


Studies on lectins. XXXIV. The effect of thermal treatment on the lectin of lentil seeds (Lens esuclenta Moench).
The lectin of lentil seeds (Lens esculenta Moench) dissociates into subunits upon incubation of its solution at temperatures above 50 degrees C. The dissociation is accompanied by precipitation of the heavy subunit, release of Mn2+ from the protein molecule and an almost complete loss of erythroagglutinating activity. Addition of Mn2+ or D-glucose to the lectin solutions has a partially protective effect on the dissociation and inactivation.


Multiple functions of volatiles in flowers and leaves of Elsholtzia rugulosa (Lamiaceae) from southwestern China.
Although the roles of volatile compounds have been examined separately in plant-herbivore or plant-pollinator interactions, few studies have focused on how plant scents can attract effective pollinators, repel ineffective pollinators, and defend against attacks by insect herbivores. We explored the functional significance of volatile compounds that impart a strong odor to Elsholtzia rugulosa, a shrub species in southwestern China. We monitored the pollinating honey bee Apis cerana, as well as two occasional visitors - Vespa velutina and a Bombus sp. - and an herbivorous beetle Oxycetonia jocunda. Behavior experiments using Y-tubes showed that honey bees were attracted primarily by floral scent while hornets and bumble bees were repelled by both the flowers and leaves. Analysis via gas chromatography-mass spectrometry revealed that these tissue types differed in their compositions and relative amounts of volatile compounds. When the plants were damaged, the average relative amounts of Elsholtzia ketone rapidly increased in the flowers and leaves. Furthermore, herbivorous beetles were strongly repelled by damaged tissues, suggesting a potential defense signaling function by these compounds. Our findings again demonstrate that scents have multiple functions in the interactions among plants and insects.