Nivolumab plus ipilimumab plus cabozantinib triplet combination for patients with previously untreated advanced renal cell carcinoma: Results from a discontinued arm of the phase III CheckMate 9ER trial.
The phase III CheckMate 9ER trial originally included a nivolumab plus ipilimumab plus cabozantinib triplet arm, which was discontinued early due to the evolving treatment landscape for first-line advanced renal cell carcinoma (aRCC). We report an exploratory analysis of patients randomised to the triplet regimen before enrolment discontinuation. Patients with clear-cell aRCC received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) Q3W for four cycles with once-daily cabozantinib (40 mg), then nivolumab (240 mg) Q2W plus once-daily cabozantinib (40 mg). CheckMate 9ER primary (progression-free survival [PFS] by blinded independent central review [BICR]) and key secondary (overall survival [OS], objective response rate [ORR] by BICR, and safety) endpoints were applied, along with investigator-assessed PFS and ORR. Fifty patients were randomised to the triplet regimen. After a median follow-up of 39.1 months (range, 33.4-44.5), median PFS (95% CI) was 9.9 (5.7-16.8) months by BICR and 13.9 (7.3-24.7) months by investigator; median OS (95% CI) was 37.0 (31.8-not estimable) months. ORR (95% CI) was 44.0% (30.0-58.7; complete response, 8.0%) by BICR and 48.0% (33.7-62.6; all partial responses) by investigator. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 84.0%, most commonly alanine aminotransferase increased (20.0%), aspartate aminotransferase increased (16.0%), and hepatotoxicity (16.0%). Grade 3-4 hepatic immune-mediated AEs occurred in 40.0%. There were no grade 5 TRAEs. These results suggest that the nivolumab plus ipilimumab plus cabozantinib triplet combination has clinical activity in patients with previously untreated aRCC, although monitoring of overlapping toxicities will be important in future studies of this regimen. gov registration: NCT03141177.


Influence of a growing ascitic tumor in mice on the distribution of injected 65Zn: role of the quantity of zinc administered.
65-Zinc distribution was studied in different organs of either healthy mice or mice bearing an ascitic tumor. This study clearly showed that zinc distribution differs between healthy and tumoral mice. Moreover, zinc distribution in the different organs of the mice is modified by the quantity administered.


Impact de la grossesse sur le psoriasis.
During pregnancy there is spontaneous improvement in various inflammatory diseases, including psoriasis for the majority of women. Hormonal changes during pregnancy may play a role in improving psoriasis by promoting a state of transient immune tolerance, promoting a TH2-type response, and lowering the inflammatory cascades of psoriasis. It is more the ratio of estrogens to progesterone than the respective relative levels of the circulating hormones themselves that may improve psoriasis. There is a risk of psoriasis flare in the first few months postpartum. Breastfeeding seems to have less influence on the natural history of skin lesions.


POEMS syndrome treated with melphalan high-dose therapy and autologous blood stem cell transplantation: a single-institution experience.
The acronym POEMS syndrome stands for a rare multi-system disorder, comprised of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. Here, we present a single-center report of a series of five POEMS patients treated with melphalan high-dose therapy (HDT) with subsequent autologous blood stem cell transplantation (ABSCT). After a median follow-up of 52 months from time of diagnosis (range, 15-192) and a median follow-up of 18 months after ABSCT (range, 11-120), all patients were alive. Overall, no severe transplantation-associated complications such as engraftment syndrome or peri- or post-transplant death were noted. In two cases, HDT followed by ABSCT resulted in a complete hematologic response; in the additional three cases, partial responses (PR) were achieved including one very good hematologic PR. Only one patient with initial PR developed progressive disease nearly 2.5 years after transplantation. Consequently, a second HDT with ABSCT was successfully applied resulting in clinical improvement and hematologic PR. In line with previous single-center reports, melphalan HDT followed by ABSCT proved to be a first-line treatment option with tolerable side effects in severely affected POEMS patients with progressing symptoms.


The role of oxidative stress and NADPH oxidase in cerebrovascular disease.
The study of reactive oxygen species (ROS) and oxidative stress remains a very active area of biological research, particularly in relation to cellular signaling and the role of ROS in disease. In the cerebral circulation, oxidative stress occurs in diverse forms of disease and with aging. Within the vessel wall, ROS produce complex structural and functional changes that have broad implications for regulation of cerebral perfusion and permeability of the blood-brain barrier. These oxidative-stress-induced changes are thought to contribute to the progression of cerebrovascular disease. Here, we highlight recent findings in relation to oxidative stress in the cerebral vasculature, with an emphasis on the emerging role for NADPH oxidases as a source of ROS and the role of ROS in models of disease.


Novel mutations in GJA1 in two Brazilian families with oculodentodigital dysplasia.
Oculodentodigital dysplasia (ODDD; MIM #164200), a rare genetic disorder characterized by abnormal craniofacial, dental, ocular, and digital features, is caused by mutations in GJA1 (gap junction alpha-1) gene and inherited in an autosomal dominant pattern. However, an autosomal recessive pattern is also reported. Here we described 2 families with members affected by ODDD. In the first family, the c.752G>C (p.S251T) and c.848C>T (p.P283L) heterozygous missense mutations and the c.825C>T (p.T275T) silent mutation were identified in the proband, which showed mild ODDD phenotypes, and in his mother, which displayed hemolytic anemia and thrombocytopenia. In the second family, the patients displayed typical features of ODDD, and Sanger sequencing identified a novel homozygous c.604C>T (p.R202C) missense mutation, whereas the parents carried the mutation. Together, these findings suggest that homozygous mutation in GJA1 induces a more severe ODDD phenotype, though interfamilial phenotype variability was observed, whereas compound heterozygous mutations in GJA1 cause a mild phenotype.


Conjugated estrogen plus medroxyprogesterone does not impair blood rheological properties in hypertensive postmenopausal women.
Hypertension and estrogens are both prothrombotic. We used the microchannel method to investigate whether hormone replacement therapy (HRT) with conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) affects blood flow through the microchannels in hypertensive postmenopausal women being treated with antihypertensive drugs and in normotensive postmenopausal women. Sixty-two consecutive postmenopausal women were randomly assigned to a hypertensive HRT group (n=16), hypertensive control group (n=15), normotensive HRT group (n=16) and normotensive control group (n=15). Each HRT group received CEE 0.625 mg plus MPA 2.5 mg daily orally for 12 months. Both hypertensive groups were being treated with antihypertensive drugs before the study. Microvascular blood flow was assessed on the basis of blood passage time, the time required for 100 microl of whole blood to pass through a cylinder, was determined before and 12 months after the start of HRT by the microchannel method (micro channel array flow analyzer). CEE plus MPA therapy did not change blood passage time in any of the groups. Microscopic observation showed that the whole blood passed smoothly through the microchannels in every group. CEE plus MPA therapy may not impair blood flow through the microchannels in hypertensive postmenopausal women receiving antihypertensive drugs or in normotensive postmenopausal women. However, administration of CEE plus MPA to postmenopausal women with hypertension warrants caution against the occurrence of thromboembolic events.


Seizure or syncope: lessons over time.
A 25-year-old woman with recurrent syncopal episodes presented with a first time generalized tonic clonic (GTC) seizure. She had experienced two prior fainting spells lasting seconds and associated with diet pills and dehydration. She had another similar spell prior to falling, sustaining a laceration to the right posterior occiput, and having a witnessed GTC seizure. Her scalp electroencephalography (EEG) showed left temporal slowing with sharp features. T1-weighted and T2-weighted MRI revealed two moderately enhancing focal lesions within the left frontal and temporal regions. These findings raised the possibility of an underlying seizure focus. Repeat imaging studies of this patient 1 month later, however, demonstrated resolution of these findings and an area of encephalomalacia, consistent with a traumatic coup contrecoup injury. A repeat EEG was normal. Therefore, the cause of the loss of consciousness was due to syncope with the consequent head injury giving rise to an isolated seizure. Understanding the underlying cause of a seizure is important in dictating treatment. In this setting the patient was not initiated on seizure medication and has done well.


Bu-Shen-Ning-Xin decoction alleviates premature ovarian insufficiency (POI) by regulating autophagy of granule cells through activating PI3K/AKT/mTOR pathway.
To explore the therapeutic effects of Bu-Shen-Ning-Xin decoction (BSNXD) on POI and the underlying mechanism. VCD was used to induce the in vivo and in vitro POI model. HE staining was used to evaluate the pathological state of ovarian tissues. ELISA was used to detect the production of hormones in the serum and granule cells (GCs). An immunohistochemical assay was used to determine the expression of ATG7 and p-AKT in the ovarian tissues. The number of oocytes in POI rats was counted. The mitochondrial membrane potential (MMP) in oocytes and GCs was detected by flow cytometry. A Western blot assay was used to measure the expression of AKT, p-AKT, p-mTOR, mTOR, S6K, p-S6K, ULK1, p-ULK1, Beclin-1, Bcl-2, LC3-II, LC3-I, ATG7, and cleaved Caspase3. The numbers of autophagosomes were detected by transmission electron microscope and autophagic flux assay. The CCK-8 assay was used to detect the cell viability. Decreased primary follicles in the ovarian tissues, elevated concentration of FSH, and LH, suppressed concentration of E2 and AMH in the serum, reduced number of oocytes, and mitochondrial dysfunction in oocytes induced by VCD were significantly reversed by BSNXD. Activated autophagy state and inhibited PI3K/AKT/mTOR pathway stimulated by VCD in both ovarian tissues and GCs were dramatically reversed by BSNXD. The protective effect of BSNXD on VCD-treated GCs was abolished by LY294002, an inhibitor of the PI3K/AKT/mTOR pathway. Our data revealed that BSNXD alleviated POI by regulating autophagy of granule cells through activating PI3K/AKT/mTOR pathway.


Distribution of specific binding of [3H]promegestone in benign prostatic hypertrophy in regard to age, race and histological differences.
Progesterone receptors were measured in BPH tissues obtained via open prostatectomy on over thirty [30] patients. Specific receptor concentration was determined by computation of the suppressible binding from the 8S region of the glycerol density gradient (centrifuged in a vertical rotor) as described by McGuire and his colleagues. Measurable progesterone receptor concentrations were obtained from all thirty specimens. These patients were subsequently categorized on the basis of several parameters including age, race, and histology of the hyperplasia. Age and race groupings demonstrated no specific distribution pattern, however, there was a marked difference in mean receptor concentration between the histological classifications.


Women's preferences for and views on decision-making for diagnostic tests.
It is unclear whether the Control Preferences Scale (CPS) provides a suitable framework for eliciting women's preferences for involvement in decision-making about diagnostic tests. The aims of this study were to assess the appropriateness of the role label approach for eliciting preferences for decision-making about diagnostic tests and to elicit women's preferences for, and views about, decision-making for diagnostic tests. In-depth, face-to-face, semi-structured interviews were conducted with 37 women who had previously participated in a population-based telephone survey. Analysis of the interview transcripts revealed that qualitative questions may be a more sensitive methodology for eliciting preferences than the role label approach as exemplified by the CPS. The analysis identified a number of issues associated with decision-making for diagnostic tests, including defining what a decision is, the rationale for the preference and factors that influence the preferred role such as the perceived seriousness of the test and potential outcomes. The role label approach used to elicit preferences for involvement in decision-making may be too simplistic. It may not fully capture the complexity of women's thoughts about test decision-making, including how they define a decision and what factors affect their preference.


Eosinophilic esophagitis in a patient with vigorous achalasia.
A patient with vigorous achalasia is presented who had marked smooth muscle hypertrophy and eosinophilic infiltration of the esophagus identical to that seen in patients with eosinophilic gastroenteritis. Eosinophilic infiltration of the esophagus probably represents a variant of the eosinophilic gastroenteritis syndrome and may predispose to an esophageal motor disorder.


Insights into the role of dual reaction sites for single Ni atom Fenton-like catalyst towards degradation of various organic contaminants.
The trade-off of Fenton-like catalysts in activity and stability remains a challenge in practical remediation applications. In this work, we successfully synthesized an efficient and stable catalyst comprised of single nickel (Ni) atoms dispersed on N-doped porous carbon (named Ni-SAs@CN) through a simple micropore confinement strategy. The catalyst exhibited outstanding catalytic performance with 25.8 min-1 turnover frequency for peroxymonosulfate (PMS) activation toward degradation of various organic pollutants (e.g., antibiotics, dyes, and plasticizers) in a wide pH range (4.5-10.8). Electron paramagnetic resonance and in situ Raman analyses demonstrated that both radical (including SO4•- and •OH) and Ni-PMS* dominated nonradical (via electron transfer) pathways played pivotal role in the decomposition of organics. The X-ray adsorption fine structure analysis and computational pieces of evidence demonstrate that the atomically dispersed NiN4 coordination is the intrinsic catalytic site for PMS activation. Meanwhile, pyrrolic N acts as a functional site to anchor target contaminants to the surface region for oxidation. In this process which is benefited from the dual active sites, the target contaminants were degraded via combined radical and nonradical pathways, which significantly boost the overall oxidation and mineralization kinetics.


Value of the facial nerve latency test in the prognosis of childhood Bell's palsy.
In the present study we evaluated the facial nerve latency test (FNLT) as a prognostic tool in cases of childhood Bell's palsy. Twenty-five children aged 4-14 years were studied. We divided our subjects into three groups according to duration of latency time (LT). Group A patients had an LT within the normal range, with average of 3.27 ms, group B a slightly prolonged LT averaging 5.7 ms, and group C a markedly prolonged LT averaging 10.5 ms. Analysis of the recovery index by group showed that group A patients experienced complete and quick recovery, while in group B 50% had complete but delayed recovery and 50% slightly impaired facial nerve function, and in group C 50% had slightly impaired function and 50% incomplete recovery. The more prolonged the LT, the worse the clinical results. The FNLT is thus a valuable prognostic tool in cases of Bell's palsy in childhood.


Increased Langerhan cell density and corneal nerve damage in diabetic patients: role of immune mechanisms in human diabetic neuropathy.
Immune mechanisms have been proposed to play a role in the development of diabetic neuropathy. We employed in vivo corneal confocal microscopy (CCM) to quantify the presence and density of Langerhans cells (LCs) in relation to the extent of corneal nerve damage in Bowman's layer of the cornea in diabetic patients. 128 diabetic patients aged 58 ± 1 yrs with a differing severity of neuropathy based on Neuropathy Deficit Score (NDS-4.7 ± 0.28) and 26 control subjects aged 53 ± 3 yrs were examined. Subjects underwent a full neurological evaluation, evaluation of corneal sensation with non-contact corneal aesthesiometry (NCCA) and corneal nerve morphology using corneal confocal microscopy (CCM). The proportion of individuals with LCs was significantly increased in diabetic patients (73.8%) compared to control subjects (46.1%), P = 0.001. Furthermore, LC density (no/mm(2)) was significantly increased in diabetic patients (17.73 ± 1.45) compared to control subjects (6.94 ± 1.58), P = 0.001 and there was a significant correlation with age (r = 0.162, P = 0.047) and severity of neuropathy (r = -0.202, P = 0.02). There was a progressive decrease in corneal sensation with increasing severity of neuropathy assessed using NDS in the diabetic patients (r = 0.414, P = 0.000). Corneal nerve fibre density (P < 0.001), branch density (P < 0.001) and length (P < 0.001) were significantly decreased whilst tortuosity (P < 0.01) was increased in diabetic patients with increasing severity of diabetic neuropathy. Utilising in vivo corneal confocal microscopy we have demonstrated increased LCs in diabetic patients particularly in the earlier phases of corneal nerve damage suggestive of an immune mediated contribution to corneal nerve damage in diabetes.


Infantile spasms associated with hemihypsarrhythmia and hemimegalencephaly.
A case of unilateral megalencephaly in a four-week-old child with infantile spasms and hemihypsarrhythmia is presented. The histological and histometrical investigations showed signs of immaturity in the cortex of the megalencephalic hemisphere.


[Hypertension and exercise].
Levels of physical activity in modern urbanized society are clearly insufficient to maintain good health, and to prevent cardiovascular and other disease. Aerobic exercise is almost completely free of secondary effects, and is a useful adjunctive therapy in treating hypertension. There are several possible mechanisms to account for the beneficial effects of exercise in reducing blood pressure, the resulting physiological effects usually being classified as acute, post-exercise or chronic. Variations in genetic background, hypertension etiology, pharmacodynamics and pharmacokinetics may explain the different blood pressure responses to exercise among hypertensive patients. The present review discusses the different pathophysiological aspects of the response to exercise in hypertensives, including its modulators and diagnostic and prognostic usefulness, as well as the latest guidelines on prescribing and monitoring exercise regimes and drug therapy in the clinical follow-up of active hypertensive patients.


The artificial bladder sphincter AS-721 for the treatment of incontinence in patients with neurogenic bladder.
An artificial sphincter was placed at the bladder neck in 9 male and 3 female patients with urinary incontinence and neurovesical dysfunction. Criteria for selection of patients included complete bladder emptying, absence of vesicoureteral reflux and normal upper urinary tracts. Of the 9 male patients 6 became continent, with an average followup of 25 months, and only 1 mechanical failure occurred. The results were less satisfactory in the 3 female patients, 2 of whom eventually required supravesical diversion. Artificial sphincters are valuable in the treatment of certain children and adults who are incontinent because the pelvic floor is damaged or denervated, even if they have neurovesical dysfunction.


Cadmium Toxicity in Wheat: Impacts on Element Contents, Antioxidant Enzyme Activities, Oxidative Stress, and Genotoxicity.
Cadmium (Cd) pollution is constantly increasing in agricultural systems due to anthropogenic activities and causes significant reductions in the yield of crop species. In this study, we aimed to determine the effect of Cd stress on growth, element contents, oxidative damage, antioxidant enzyme activities, and genotoxicity in wheat (Triticum aestivum L.). To achieve this goal, 7-day-old wheat seedlings were subjected to different concentrations of Cd(NO3)2·4H2O (250, 500, and 1000 µM) for 4 days. The results show that Cd stress induces growth inhibition, oxidative injury, and genotoxicity in wheat seedlings. Moreover, the highest concentration of Cd treatment led to a significant increase in the activities of antioxidant enzymes, except for catalase. In addition, a dramatic decrease was observed in K and Ca contents in response to Cd treatments. Overall, our findings suggest that even short-term exposure to Cd can impair key physiological processes influencing growth, oxidative homeostasis, and genomic stability in wheat.


Dynamics of size-fractionated bacterial communities during the coastal dispersal of treated municipal effluents.
Everyday huge amount of treated municipal wastewater is discharged into the coastal seawater. However, microbial biomarkers for the municipal effluent instead of the fecal species from raw sewage have not been proposed. Meanwhile, bacterial taxa for degrading large amounts of input organics have not been fully understood. In this study, raw effluent and serial water samples were collected from the coastal dispersal of two sewage treatment plants in Xiamen, China. Free-living (FL) and particle-associated (PA) bacterial communities were analyzed via high-throughput sequencing of 16S rRNA gene and quantitative PCR to measure bacterial abundance. The PA bacterial communities in our samples exhibited higher cell abundance, alpha diversity, and population dynamics than the FL bacterial communities, which supports greater environmental significance of the PA bacterial communities. Two non-fecal but typical genera in activated sludge, Zoogloea and Dechloromonas, exhibited decreased but readily detectable abundance along the effluent dispersal distance. Furthermore, the dominating microbial species near the outfalls were related to well-known marine indigenous taxa, such as SAR11 clade, OM60 clade, low-GC Actinobacteria, and unclassified Flavobacteriales, as well as the less understood taxa like Pseudohongiella and Microbacteriaceae. It is interesting that these taxa exhibited two types of correlation patterns with COD concentration. Our study suggested Zoogloea as a potential indicator of municipal effluents and also proposed potential utilizers of residual effluent COD in marine environments.


Opossum insulin, glucagon and pancreatic polypeptide: amino acid sequences.
Pancreatic hormones have been purified from the opossum, a New World marsupial. Opossum insulin contains a Leu substitution at the N-terminus of the B-chain in place of the Phe that is generally present in mammalian insulins. In addition, there are two other amino acid substitutions in the opossum insulin A-chain (positions 8 and 18) compared to pig insulin. Opossum glucagon is identical to chicken glucagon with both differing from the usual mammalian glucagon by Ser in place of Asn at its penultimate C-terminal position. Opossum PP differs from the porcine peptide in only 3 sites (position 3, 19 and 30).


Management of Intracranial Meningiomas Using Keyhole Techniques.
Keyhole craniotomies are increasingly being used for lesions of the skull base. Here we review our recent experience with these approaches for resection of intracranial meningiomas. Clinical and operative data were gathered on all patients treated with keyhole approaches by the senior author from January 2012 to June 2013. Thirty-one meningiomas were resected in 27 patients, including 9 supratentorial, 5 anterior fossa, 7 middle fossa, 6 posterior fossa, and 4 complex skull base tumors. Twenty-nine tumors were WHO Grade I, and 2 were Grade II. The mean operative time was 8 hours, 22 minutes (range, 2:55-16:14) for skull-base tumors, and 4 hours, 27 minutes (range, 1:45-7:13) for supratentorial tumors. Simpson Resection grades were as follows: Grade I = 8, II = 8, III = 1, IV = 15, V = 0. The median postoperative hospital stay was 4 days (range, 1-20 days). In the 9 patients presenting with some degree of visual loss, 7 saw improvement or complete resolution. In the 6 patients presenting with cranial nerve palsies, 4 experienced improvement or resolution of the deficit postoperatively. Four patients experienced new neurologic deficits, all of which were improved or resolved at the time of the last follow-up. Technical aspects and surgical nuances of these approaches for management of intracranial meningiomas are discussed. With careful preoperative evaluation, keyhole approaches can be utilized singly or in combination to manage meningiomas in a wide variety of locations with satisfactory results.


Physiological activities of the combination of fish oil and α-lipoic acid affecting hepatic lipogenesis and parameters related to oxidative stress in rats.
We studied the combined effect of fish oil and α-lipoic acid on hepatic lipogenesis and fatty acid oxidation and parameters of oxidative stress in rats fed lipogenic diets high in sucrose. A control diet contained a saturated fat (palm oil) that gives high rate of hepatic lipogenesis. Male Sprague-Dawley rats were fed diets supplemented with 0 or 2.5 g/kg α-lipoic acid and containing 0, 20, or 100 g/kg fish oil, for 21 days. α-Lipoic acid significantly reduced food intake during 0-8 days but not the later period of the experiment. Fish oil and α-lipoic acid decreased serum lipid concentrations and their combination further decreased the parameters in an additive fashion. The combination of fish oil and α-lipoic acid decreased the activity and mRNA levels of hepatic lipogenic enzymes in an additive fashion. Fish oil increased the parameters of hepatic fatty acid oxidation enzymes. α-Lipoic acid appeared to antagonize the stimulating effects of fish oil of fatty acid oxidation through reductions in the activity of some fatty acid oxidation enzymes. α-Lipoic acid attenuated fish oil-dependent increases in serum and liver malondialdehyde levels, and this compound also reduced the serum 8-hydroxy-2'-deoxyguanosine level. α-Lipoic acid affected various parameters related to the antioxidant system; fish oil also affected some of the parameters. The combination of fish oil and α-lipoic acid effectively reduced serum lipid levels through the additive down-regulation of hepatic lipogenesis. α-Lipoic acid was effective in attenuating fish oil-mediated oxidative stress.


Effect of tumor-associated macrophages on the pyroptosis of breast cancer tumor cells.
Macrophages are immune cells with high plasticity that are widely distributed in all tissues and organs of the body. Under the influence of the immune microenvironment of breast tumors, macrophages differentiate into various germline lineages. They exert pro-tumor or tumor-suppressive effects by secreting various cytokines. Pyroptosis is mediated by Gasdermin family proteins, which form holes in cell membranes and cause a violent inflammatory response and cell death. This is an important way for the body to fight off infections. Tumor cell pyroptosis can activate anti-tumor immunity and inhibit tumor growth. At the same time, it releases inflammatory mediators and recruits tumor-associated macrophages (TAMs) for accumulation. Macrophages act as "mediators" of cytokine interactions and indirectly influence the pyroptosis pathway. This paper describes the mechanism of action on the part of TAM in affecting the pyroptosis process of breast tumor cells, as well as its key role in the tumor microenvironment. Additionally, it provides the basis for in-depth research on how to use immune cells to affect breast tumors and guide anti-tumor trends, with important implications for the prevention and treatment of breast tumors. Video Abstract.


First-episode, recurrent, and asymptomatic herpes simplex infections.
Genital herpes simplex virus infections should be classified into first-episode and recurrent infections. First-episode infections include true primary infections in patients with seronegative results who have never been infected with any type of herpes and nonprimary first-episode infections in patients who have been infected before and have serum antibody and humoral immunity, an example being genital infection with type 2 in adolescence after orolabial infection with type 1 in childhood. First-episode infections show more extensive disease, more systemic symptoms, and greater viral shedding than do recurrent infections. Ten percent to 15% of patients with first-episode primary genital herpes have oropharyngeal infections with the same virus strain. Herpesvirus can be isolated from the urethra in about 30% of male patients with first-episode infections. In recurrent vulvar herpes, virus can be isolated from the cervix in 10% to 15% of patients. Many genital lesions that clinically suggest something else turn out to be herpes; herpes may be diagnosed 5% of the time clinically but cultures are positive 14% of the time. Primary genital herpes type 2 infections recur about 95% of the time whereas type 1 infections recur about 50% of the time. Recurrences are highly unpredictable from patient to patient and time to time. The role of asymptomatic shedding in the spread of herpes is a major area for future study. Antiviral treatment is probably going to change the epidemiology of herpetic infections very little.


Routine endoscopic surveillance for local recurrence of rectal cancer is futile.
National Comprehensive Cancer Network guidelines for rectal adenocarcinoma regarding routine surveillance with proctoscopy for local recurrence have been evolving. The purpose of this study was to examine the utility of rectal surveillance. This is a single-center, retrospective review of patients (2004 to 2011) who underwent total mesorectal excision for rectal cancer. The primary end point was cancer recurrence, with detection method(s) noted. The number of surveillance procedures was collected. The study included 112 patients. There were no local recurrences identified by rectal surveillance. There were 1 local recurrence and 17 distant recurrences (16%). The local recurrence was identified by carcinoembryonic antigen and symptoms. There were 20 anoscopies, 44 proctoscopies, and 495 flexible sigmoidoscopies performed, with estimated charges of $266,000. Rectal surveillance at this center was not beneficial. This study supports the recent (2015) change in the National Comprehensive Cancer Network guidelines, which no longer recommend routine rectal surveillance and challenge other society guidelines.


proBDNF Attenuates Hippocampal Neurogenesis and Induces Learning and Memory Deficits in Aged Mice.
Mature brain-derived neurotrophic factor has shown promotive effect on neural cells in rodents, including neural proliferation, differentiation, survival, and synaptic formation. Conversely, the precursor of brain-derived neurotrophic factor (proBDNF) has been emerging as a differing protein against its mature form, for its critical role in aging process and neurodegenerative diseases. In the present study, we investigated the role of proBDNF in neurogenesis in the hippocampal dentate gyrus of aged mice and examined the changes in mice learning and memory functions. The results showed that the newborn cells in the hippocampus revealed a significant decline in proBDNF-treated group compared with bovine serum albumin group, but an elevated level in anti-proBDNF group. During the maturation period, no significant change was observed in the proportions of phenotype of the newborn cells among the three groups. In water maze, proBDNF-treated mice had poorer scores in place navigation test and probe test, compared with those from any other group. Thus, we conclude that proBDNF attenuates neurogenesis in the hippocampus and induces the deficits in learning and memory functions of aged mice.


Fascioliasis problems in ruminants in Rio Grande do Sul, Brazil.
The economic importance of fascioliasis in the livestock industry in the state of Rio Grande do Sul was assessed through the Federal meat inspection at major slaughter houses. Annual average rates of the livers condemned by Fasciola hepatica infection at the houses in the state have been recorded as 12-13% in cattle and 7% in sheep, respectively. Many farms in the provinces of the frontier regions of Brazil with Uruguay are contaminated with F. hepatica and acute fascioliasis with a high mortality among sheep flocks frequently occurs during the wet and cold winter season in the lowland areas of the regions. The two Lymnaeid snails, Lymnaea viatrix and L. columella are distributed in the state and act as intermediate hosts of F. hepatica. The former species, called the "mud snail", is more predominant than the latter: "pond snail".


Effect of post-treatments with caffeine during G2 on the frequencies of chromosome-type aberrations produced by X-rays in human lymphocytes during G0 and G1.
Human lymphocytes were irradiated with X-rays in G0 and G1, grown in the presence of 5-bromodeoxyuridine, and harvested at different times from 48 to 80 h after stimulation. Some cultures were exposed to 2.5-5 mM caffeine during the last 3 h before harvesting. The frequencies of chromosome-type aberrations were scored in first division (M1) metaphases. The post-treatment with caffeine increased the frequencies of mitoses and chromosome-type aberrations in irradiated cultures. The results suggest that cells carrying chromosome-type aberrations are delayed in G2 and that caffeine increases the frequencies of aberrations in dividing cells by removing this G2-block.


Endogenous growth inhibition of angiogenesis in brain tumors.
The growth inhibition of remote metastases by a primary tumor is known as endogenous growth inhibition leading to tumor dormancy. Such a phenotype has not been described in primary malignant gliomas. However, although glioma cells have frequently spread to other parts of the brain at the time of diagnosis, formation of solid secondary tumors is uncommon. We hypothesize that a dormant population of distant glioma cells exist. The purpose of this study was to investigate whether primary gliomas could inhibit secondary tumor formation. Subcutaneous tumors from human gliomas were grown as xenografts in Swiss nude mice. At a tumor size of at least one cm(3), the same amount of cells was injected into the contralateral flank or into the right cerebral hemisphere. Control mice without a primary tumor were injected with tumor cells either into the right flank, the right hemisphere, or bilaterally subcutaneously. Only one of 18 human gliomas demonstrated inhibition at the subcutaneous and intracerebral secondary implantation sites. Growth inhibition of the secondary tumors was accompanied by a significant reduction in microvessel density, upregulation of vascular endothelial growth factor mRNA and downregulation of basic fibroblast growth factor mRNA. Therefore, endogenous inhibition of secondary tumors may represent a rare phenotype in malignant glioma.


Radiocarbon Palaeolithic Europe database: A regularly updated dataset of the radiometric data regarding the Palaeolithic of Europe, Siberia included.
At the Berlin INQUA Congress (1995) a working group, European Late Pleistocene Isotopic Stages 2 & 3: Humans, Their Ecology & Cultural Adaptations, was established under the direction of J. Renault-Miskovsky (Institut de Paléontologie humaine, Paris). One of the objectives was building a database of the human occupation of Europe during this period. The database has been enlarged and now includes Lower, Middle and Upper Palaeolithic sites connecting them to their environmental conditions and the available chronometric dating. From version 14 on, only sites with chronometric data were included. In this database we have collected the available radiometric data from literature and from other more restricted databases. We try to incorporate newly published chronometric dates, collected from all kind of available publications. Only dates older than 9500 uncalibrated BP, correlated with a "cultural" level obtained by scientific excavations of European (Asian Russian Federation included) Palaeolithic sites, have been included. The dates are complemented with information related to cultural remains, stratigraphic, sedimentologic and palaeontologic information within a Microsoft Access database. For colleagues mainly interested in a list of all chronometric dates an Microsoft Excel list (with no details) is available (Tab. 1). A file, containing all sites with known coordinates, that can be opened for immediate use in Google Earth is available as a *.kmz file. It will give the possibility to introduce (by file open) in Google Earth the whole site list in "My Places". The database, version 27 (first version was available in 2002), contains now 13,202 site forms, (most of them with their geographical coordinates), comprising 17,022 radiometric data: Conv. 14C and AMS 14C (13,144 items), TL (678 items), OSL (1050 items), ESR, Th/U and AAR (2150 items) from the Lower, Middle and Upper Palaeolithic. All 14C dates are conventional dates BP. This improved version 27 replaces the older version 26.


Comparison of the replication of distinct strains of human coronavirus OC43 in organotypic human colon cells (Caco-2) and mouse intestine.
Three strains of human coronavirus (HCV) OC43 were compared for their ability to cause enteric infections and to induce interferon alpha (IFN alpha) using the Caco-2 human colon carcinoma cell line which exhibits spontaneous epithelial differentiation in vitro. MRC-5 cell culture grown stocks were prepared from: 1. CV Paris, a strain of OC43 recovered from an outbreak of necrotizing enterocolitis in newborns. 2. CV Mb, a neurotropic strain of OC43 which exhibits strict neuronal specificity in murine neuronal cell cultures. 3. CV Rd, a strain of OC43 which grows to a high titer in human rhabdomyosarcoma (RD) cells. Immunofluorescent staining for nucleocapsid antigen and plaque assay in MRC-5 cells was used to detect viral replication. BG-9 (human foreskin) cells challenged with vesicular stomatitis virus were used to detect IFN alpha production by human peripheral blood monocytes (PBMC) stimulated by virus infected Caco-2 cells. Caco-2 cells infected with virus at a multiplicity of infection of 0.5 yielded 10(4.6) and 10(4.4) plaque forming units/ml (pfu/ml) with CV Rd and CV Paris respectively, while CV Mb yielded only 10(3) pfu/ml. Caco-2 cells infected with CV Rd induced 64 IU/ml of IFN alpha in PBMC while these cells infected with CV Paris induced less than 2 IU/ml IFN alpha. In cells infected with CV Mb 4 IU/ml IFN alpha was detected. The results suggest that a lack of IFN alpha induction by CV Paris may be an indicator of its enteropathogenic potential.(ABSTRACT TRUNCATED AT 250 WORDS)


Congenital deficiency of the ulna.
Twenty-three patients with ulnar ray deficiency were studied and the deformities described by combining Kummel's and Swanson's classifications. An individualized, functionally oriented management program is recommended with early resection of the fibrocartilaginous remnant to prevent shortening, radial bowing, and possible malrotation. Rotational deformity can be corrected by wedge osteotomy, rotation osteotomy, or proximal radial ulnar synostosis. Improved motion at the elbow can be obtained by release of contractures or resection of the radial head. Wrist deformity may require resection of the ulnar remnant and a wedge osteotomy of the radius.


The Effects of Resveratrol on Oxidative Stress Markers: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Recent trial studies have found that resveratrol supplementation beneficially reduces oxidative stress marker, but, there is no definitive consensus on this context. The present systematic review and meta-analysis aimed to investigate the effect of resveratrol supplementation on oxidative stress parameters. We searched databases of Pubmed, Scopus and Cochrane Library up to December 2018 with no language restriction. Studies were reviewed according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) and Cochrane handbook. To compare the effects of resveratrol with placebo, weighted mean difference (WMD) with 95% confidence intervals (CI) were pooled based on the random-effects model. Among sixteen clinical trials, we found that resveratrol supplementation increased GPx serum levels significantly (WMD: 18.61; 95% CI: 8.70 to 28.52; P<0.001) but had no significant effect on SOD concentrations (WMD: 1.01; 95% CI: -0.72 to 2.74; P= 0.25), MDA serum levels (WMD: -1.43; 95% CI: -3.46 to 0.61; P = 0.17) and TAC (WMD: -0.09; 95% CI: -0.29 to 0.11; P = 0.36) compared to placebo. Finally, we observed that resveratrol supplementation may not have a clinically significant effect on oxidative stress. However, the number of human trials is limited in this context, and further large prospective clinical trials are needed to confirm the effect of resveratrol supplement on oxidative stress markers.


Lung growth and maturation in experimental oligohydramnios in the rat.
On day 16 of gestation the amniotic sacs of either the right or left uterine horns of timed-pregnant Sprague-Dawley rats were punctured with a 20-gauge needle. The fetuses of the opposite horn served as controls. On day 21 of gestation (1 day prior to natural delivery), the fetuses were delivered by Cesarean section. Amniotic sac puncture resulted in a significant loss of amniotic fluid. Fetal growth retardation occurred. Lung growth was specifically retarded, as indicated by significantly reduced lung weight to body weight ratios and lung volume to body weight ratios following amniotic sac puncture. There appeared to be no effect on the structural units of the lung, since no differences between control and experimental fetal lungs were observed in terms of deoxyribonucleic acid, nonconnective tissue protein, total phospholipid, and disaturated phosphatidylcholine per gm dry lung weight. The ratios of disaturated phosphatidylcholine to total phospholipid and nonconnective tissue protein to deoxyribonucleic acid were unchanged. The volume proportions of saccular air, saccular wall, bronchial and bronchiolar air and nonparenchyma, peripheral airspace size, and surface-to-volume ratio were also unchanged. Thus loss of amniotic fluid significantly affected lung growth, more than it affected overall body growth, without having an effect on lung maturation.


Review of Recommended Treatment of Uterine Carcinosarcoma.
Surgery is the primary treatment for uterine carcinosarcoma (UCS). Lymphadenectomy should be performed for staging purposes in tumors apparently confined to the uterus. Most studies found that lymphadenectomy is of therapeutic value. The therapeutic value of cytoreduction to no residual macroscopic disease in advanced UCS is based mostly on small retrospective uncontrolled studies. Postoperative adjuvant therapy should be considered for all stages of UCS. Adjuvant pelvic radiotherapy may reduce locoregional recurrences. However, this does not translate into improved overall survival since most recurrences are distant outside the irradiated field, and the survival rates remain poor, the 5-year overall survival being about 50%. Several adjuvant platin-based combination chemotherapy schedules such as cisplatin/ifosfamide, ifosfamide/paclitaxel, and paclitaxel/carboplatin have been found to be an effective mode of adjuvant treatment. Multimodal therapy (i.e., adjuvant chemotherapy plus radiotherapy) has also been shown to be effective. Most studies dealing with adjuvant treatment are retrospective and prospective randomized controlled trials (i.e., phase III studies) comparing that between the various adjuvant chemotherapy schedules and between them and multimodal treatment are lacking. Quality of life with the various treatment modalities needs also to be assessed. An effective targeted therapy has so far not been found. In spite of the multiple studies with regard to the treatment of UCS published during the last 15 years, the optimal management of UCS is still not established.


Analyses of red fermented rice (angkak) and report of a newMonascus metabolite.
A HPLC-based method for the analysis of red fermented rice and results obtained with it are presented. Formation of citrinin, red, orange and yellow pigments byMonascus depends on the culture substrate. Citrinin and some pigments are decomposed by heat. A newMonascus metabolite, monascodilone, its structure and preliminary data on its toxicity are reported.


Multi-element concentrations in plant parts and fluids of Malaysian nickel hyperaccumulator plants and some economic and ecological considerations.
Information about multi-elemental concentrations in different plant parts of tropical Ni hyperaccumulator species has the potential to provide insight into their unusual metabolism relative to a range of essential and non-essential elements, but this information is scant in the literature. As Ni hyperaccumulation, and possibly co-accumulation of other toxic elements, has been hypothesized to provide herbivore (insect) protection, there is a need to quantify a range of these elements in plant tissues and transport fluids to at least verify the possibility of this explanation. In this study, multiple elements were analyzed in a range of different plant parts and transport fluids from Ni hyperaccumulator species collected from Sabah (Malaysia). The results show preferential accumulation of Ni in leaves over woody parts, but the highest concentrations were found in the phloem tissue (up to 7.9 % in Rinorea bengalensis) and phloem sap (up to 16.9 % in Phyllanthus balgooyi), visible by a bright green coloration in the field fresh material. The amount of Ni contained in one mature R. bengalensis tree was calculated at 4.77 kg. The high Ni concentration in the flowers of Phyllanthus securinegoides could affect insect floral visitors and pollination. High concentrations of Ni in the seeds of this species also could supply the seedling with Ni and aid in herbivory protection during the first stages of development. Foliar Ca and Ni in P. cf. securinegoides and R. bengalensis are positively correlated. Low accumulation of Ca is desirable for phytomining but concentrations of Ca are high in most Ni hyperaccumulators examined, and this could have consequences for the economic viability of Ni extraction from bio ore if these species were to be used as 'metal crops'.


Efficacy and Safety of Antiplatelet Therapies in Symptomatic Peripheral Artery Disease: A Systematic Review and Network Meta-Analysis.
Clopidogrel monotherapy is guideline-recommended in symptomatic peripheral artery disease (PAD). The advent of new antithrombotic strategies prompts an updated analysis of available evidence on antiplatelet therapy for PAD. We searched MEDLINE, Embase and CENTRAL through January 2019 for randomised controlled trials and observational studies comparing antiplatelet therapies as monotherapy, dual therapy, or combination with anticoagulants. Efficacy (major adverse cardiovascular events, acute or chronic limb ischaemia, vascular amputation, peripheral revascularisation) and safety (all-cause mortality and overall bleeding) outcomes were evaluated via Bayesian network meta-analyses. We analysed 26 randomised controlled trials. Clopidogrel (hazard ratio, HR, 0.78; 95% credible interval [CrI] 0.65-0.93) and ticagrelor (HR 0.80; 95% CrI 0.65-0.98) significantly reduced major adverse cardiovascular events risk compared with aspirin. No significant difference was observed for dual antiplatelet therapy with clopidogrel and aspirin. Vorapaxar significantly reduced limb ischaemia and revascularisation compared with placebo, while dual antiplatelet therapy with clopidogrel and aspirin showed a trend for reduced risk of amputation compared with aspirin (risk ratio 0.68; 95% CrI 0.43-1.04). For all-cause mortality, picotamide, vorapaxar, dipyridamole with aspirin, and ticlopidine showed a significantly lower risk of all-cause mortality vs aspirin. Clopidogrel and ticagrelor showed similar overall bleeding risk vs aspirin, while dual antiplatelet therapy with clopidogrel and aspirin significantly increased bleeding risk. This updated network meta-analysis confirms that clopidogrel significantly decreases the risk of major adverse cardiovascular events compared with aspirin, without increasing bleeding risk. Clopidogrel should remain a mainstay of PAD treatment, at least in patients at higher bleeding risk.


Literature review: Imaging in prostate cancer.
Imaging plays an increasingly important role in the detection and characterization of prostate cancer (PC). This review summarizes the key conventional and advanced imaging modalities including multiparametric magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging and tries to instruct clinicians in finding the best image modality depending on the patient`s PC-stage. We aim to give an overview of the different image modalities and their benefits and weaknesses in imaging PC. Emphasis is put on primary prostate cancer detection and staging as well as on recurrent and castration resistant prostate cancer. Results from studies using various imaging techniques are discussed and compared. For the different stages of PC, advantages and disadvantages of the different imaging modalities are discussed. Moreover, this review aims to give an outlook about upcoming, new imaging modalities and how they might be implemented in the future into clinical routine. Imaging patients suffering from PC should aim for exact diagnosis, accurate detection of PC lesions and should mirror the true tumor burden. Imaging should lead to the best patient treatment available in the current PC-stage and should avoid unnecessary therapeutic interventions. New image modalities such as long axial field of view PET/CT with photon-counting CT and radiopharmaceuticals like androgen receptor targeting radiopharmaceuticals open up new possibilities. In conclusion, PC imaging is growing and each image modality is aiming for improvement.


Prognostic Value of EGFR Exon-20 Insertions in Czech Patients With Advanced Non-small Cell Lung Cancer.
Per literature, patients with epidermal growth factor receptor (EGFR) exon-20 insertions respond poorly to tyrosine kinase inhibitors (TKIs). This study analyzed real-world data to examine the prognostic and predictive value of these mutations. We conducted a retrospective cohort study using Czech TULUNG Registry data, with data on multiple mutation types, collected in 2011-2020. We analyzed 554 (95.85%) patients with EGFR exon-19 deletions or exon-21 L858R substitutions and 24 (4.15%) patients with exon-20 insertions who received first-line high-value therapies. We summarized clinical characteristics and outcomes in all patients and by cohort. The risk of progression was statistically significantly higher (86%) in the exon-20 insertion cohort compared to the cohort with other mutations. Although not statistically significant, the risk of death was 44% higher in patients with exon-20 insertions. Advanced NSCLC patients with rare EGFR exon-20 insertions have a high risk of progression.


Hepatitis B Virus Seroprevalence Among Children With Cancer in Sudan.
The seroprevalence of hepatitis B among children with cancer in Sudan is unknown. The aim of this study was to detect the seroprevalence of hepatitis B virus (HBV) infection in children with malignancy and its correlation with different risk factors. This study included 178 children with malignancy presenting to the Radioisotope Center in Khartoum during the period of May-July 2011. Sixty-four healthy children served as controls. Sera from patients and controls were investigated for HBV total anti-core antibody, HBV surface antigen (HBsAg), and HBV e antigen (HBeAg). HBV total anti-core antibody was positive in 71/178 (39.9%), HBsAg was positive in 38 (21.3%), and HBeAg was positive in 19 (10.7%). Blood product transfusion, surgical exposure, chemotherapy, malignancy type, and sex did not affect the seroprevalence of HBV in this study. Vaccinated children had reduced rates of exposure compared to non-vaccinated patients. There is a high seroprevalence of HBV in children with malignancies in Sudan. Vaccination appears to play a major protective role.


Two-in-one ultraviolet persistent luminescent catalyst suitable for high concentration photodegradation.
Heterogeneous photodegradation is limited at high catalyst concentrations because of the scattering and reflection of the particulate catalysts. To further improve the efficiency of photodegradation and the use of space in photoreactors at high catalyst concentrations, Ga3+ was doped into Zn2SiO4 to introduce positively charged traps to capture photo-generated electrons and, thus, achieve long lifetime charge separation. In this strategy, Zn2SiO4:Ga3+ was obtained as a two-in-one (persistent luminescence and catalysis) persistent photocatalyst for the efficient photodegradation of a household insecticide, permethrin. Zn2SiO4:Ga3+ possesses an UV afterglow property. Zn2SiO4:Ga3+ can store UV irradiation energy as long lifetime separated electron/hole pairs at the solution surface and then deliver this energy deep into the bulk of the solution, thus taking full advantage of the photoreactor. High catalyst concentrations are preferred for improving the persistent photodegradation efficiency. The UV persistent photocatalytic strategy and the persistent Zn2SiO4:Ga3+ catalyst are significant for designing fast photocatalytic reactors with high catalyst concentrations.


Intramedullary Flexible Nailing for Diaphyseal Fractures of Forearm Bones in Children.
Objectives Most of the fractures of the bones of the forearm in children are successfully treated conservatively with closed reduction and casting. The outcomes remain variable and the patients may require additional fracture manipulation or formal surgical intervention due to residual angulations. The present study assesses the radiological and functional outcomes of treating displaced forearm fractures in children with intramedullary flexible titanium elastic nailing. Methods A total of 31 patients aged between 7 and 15 years old with displaced forearm fractures underwent flexible titanium elastic nailing. The patients were followed-up for a mean period of 8.51 months (range: 6-12 months) and were assessed for radiological and functional outcomes. The Price criteria were used to assess the functional outcome. Results Out of 31 patients, 21 patients underwent closed reduction, and 10 required a minimal opening of the fracture site during reduction. A total of 29 patients had excellent results with normal forearm and elbow range of motion (ROM), and 2 patients had good results. In all patients, good radiological union was seen at an average time of 7.9 weeks. Five patients had minor complications, such as skin irritation over the prominent ulnar nail ( n = 2), superficial nail insertion site infection ( n = 2), and backing out of the ulnar nail ( n = 1), requiring early removal. Conclusion Flexible nailing is an efficient application of internal fixation for shaft fractures of both bones of the forearm in children, enabling early mobilization and return to the normal activities of the patients, with low and manageable complications.


Perception of Nursing Activities That Contribute to the Quality of Care: Validity and Reliability Testing of the French Version.
Background and purpose: Measuring nurses' perceptions of the activities contributing to the quality of care needs to be emphasized, providing visibility to professional practice and their contributions to achieving health quality. This study aimed to translate, validate, and culturally adapt the "Perception of Nursing Activities that Contribute to the Quality of Care" (EPAECQC), scale to provide a reliable instrument to assist nurse managers in measuring nurses' perceptions of their activities in French reality. Methods: A quantitative, descriptive, and cross-sectional study, in two phases, was conducted. First, by translation and cultural adaptation, and second, through the validation of the scale. Results: The factor structure of the final version was reduced to 22 items. Content and construct validity and reliability were supported by internal consistency (Cronbachs' alpha = .913). Conclusions: The results show that the final version is a reliable and valid instrument, showing a high potential to be used in research and clinical practice.


What is the magnitude of the subpopulation effect?
The effect of population subdivision on estimated match probabilities has been raised [Nature 339 (1989) 501; Am. J. Hum. Genet. 48 (1991) 819; Science 254 (1991) 1921]. Previous work [J. Forensic Sci. 39 (1994) 319; J. Forensic Sci. 39 (1994) 988; Am. J. Hum. Genet. 55 (1994) 533] has compared product rule estimates from differing databases and found that the "subpopulation" error may be of the order of a factor of 10. This approach compares an estimate with an estimate. This paper uses simulation to extend these studies by allowing a comparison to a 'true match probability' and supports the conclusion that subpopulation effects are mild. In addition the performance of recommendations 4.1 and 4.2 of NRC II [National Research Council and C.O.D.F. Science, The Evaluation of Forensic DNA Evidence, National Academy Press, Washington, DC, 1996].


Regulation of toll-like receptor 2 and 4 gene expression in murine alveolar macrophages.
The authors investigated the regulation of toll-like receptor (TLR) TLR2 and TLR4 gene expression in alveolar macrophage (AM) in response to lipopolysaccharide (LPS) or proinflammatory cytokines in vitro. Treatment of a murine AM cell line, MH-S, with LPS, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta significantly increased TLR2 mRNA expression, whereas TLR4 mRNA expression remained constant. LPS-mediated TLR2 mRNA up-regulation was attenuated by inhibition of p38 kinase (with SB203580) or nuclear factor (NF)-kappaB (with sulfasalazine or SN-50), but not by inhibition of extracellular signal-regulated kinase (with PD98059) or c-Jun N-terminal kinase (with SP600125), suggesting that LPS may induce TLR2 mRNA expression through p38 kinase and NF-kappaB activation. These results indicate that TLR2 expression up-regulated in AM in response to bacterial respiratory infections may render AM responsive to TLR2 ligands, which may accelerate the innate immunity against pathogens in the lung.


Forskolin and IBMX Induce Neural Transdifferentiation of MSCs Through Downregulation of the NRSF.
Neural differentiation of mesenchymal stem cells is a controversial phenomenon, as it would require transdifferentiation across the mesoderm-ectoderm barrier. However, several laboratories have observed that MSCs are able to be induced to express neural characteristics. Previously, we demonstrated that the cAMP-elevating agents, forskolin and IBMX, induced neural-like differentiation of MSCs, including expression of neural markers and increased sensitivity to neurotransmitters. However, due to the broad range of effects that forskolin and IBMX can elicit through the intracellular second messenger, cAMP, a better mechanistic understanding is required. Here, we show that neural induction by forskolin and IBMX is dependent on downregulation of expression of the master transcriptional regulator, neuron restrictive silencer factor (NRSF), and its downstream target genes. Since silencing of NRSF is known to initiate neural differentiation, it suggests that forskolin and IBMX result in transdifferentiation of MSCs into a neural lineage.


[Clinical experience and results of ESWL treatment for 1.000 consecutive patients with the Siemens Lithostar Modularis].
We describe the outcome of the treatment of 1.000 consecutive patients treated since may 2000 to december 2003 with Siemens Lithostar Modularis to evaluate the efficacy of this new lithotripter 60.5% male and 39.5% female's patients were treated. Average age of 53.5 years old. 44.1% of the urinary stones were located on the right side and 55.9% on the left. The mean size of the stones was 1.22 +/- 0.74 cm with 59% lesser than 1 cm, 27.6% between 1 and 2 cm and 13.4% bigger than 2 cm. Mean number of sessions required were 1.6. There were differences in the number of sessions related to the size of the lithiasis, 1.3 session in the group of lithiasis smaller than 1 cm and 2.01 sessions in the group bigger than 1 cm. The stones that required less number of sessions were located in the ureter and upper calyx. 71.2% of the patients were stone free after one treatment. Siemens Lithostar Modularis has the adventages of a great confort of the patient during the procedure, better image because of a very good cuality of the fluoroscopy and the main point is a great comminution of the stone doing very easy the elimination of the fragments achieving a stone free rate of more than 90% in our experience, decreasing the need of auxiliary manoeuvres and the leng of the treatment.


Activation of neuroprotective pathways by metabotropic group I glutamate receptors: a potential target for drug discovery?
Stroke neuroprotection trials suggest that pharmacological manipulations of a single neuroprotective mechanism are generally ineffective and that new approaches, possibly involving simultaneous manipulations of multiple mechanisms, need to be sought. To identify optimal components for such a multipronged approach, we studied NMDA receptor activation-induced cell death in organotypic hippocampal culture preparations as a model of excitotoxicity. Metabotropic group I glutamate receptor (mGluR) activation by their selective agonist, (S)-3,5-dihydroxyphenylglycine (DHPG), resulted in concentration-dependent reduction of nerve cell susceptibility to NMDA-mediated injury (neuroprotective effect). The neuroprotection was mediated primarily by mGluR1, required phospholipase C activation, was inhibited by cholesterol-containing methyl-beta-cyclodextrin treatment, and occluded by antipsychotic quetiapine. It was associated with suppression of NMDA currents and prolongation of GABA(A) receptor-mediated currents in DHPG-treated cultures. cDNA microarray analysis of 1128 brain-relevant genes revealed that mGluR-mediated neuroprotection was associated with simultaneous activation of endocytosis, and inactivation of inflammation, cell adhesion, cell death, and transcription-related genes. Antisense inhibition of Rab5b, a gene coding for a small GTPase associated with endocytosis, significantly reduced the mGluR-mediated neuroprotection. These findings expand our understanding of the role that mGluRs play in regulation of nerve cell susceptibility to injury and should facilitate the design of novel therapeutic strategies for stroke and other neurodegenerative diseases.


Correlation among the indices of high-resolution computed tomography, pulmonary function tests, pulmonary perfusion scans and exercise tolerance in cases of chronic pulmonary emphysema.
Mismatched distribution of pulmonary blood flow is a common characteristic in emphysematous patients. But few reports have mentioned the relationships between the morphological changes in the lungs as assessed by high-resolution computed tomography (HRCT), pulmonary blood flow (PBF) scan and the indices of exercise tolerance. We investigated these relationships. Pulmonary function tests (PFT), HRCT, single photon emission computed tomography ((99m)SPECT) and treadmill exercise tests were performed on emphysematous patients, and the correlations between these examinations were studied. We evaluated 20 patients (M 18, F 2, age 66 +/- 8.0 years). CT evaluation was performed according to the grade of emphysematous change. (99m)SPECT was performed to evaluate mismatched PBF by the score method. The better flow of the middle lobe was selected to be the standard lobe for the basic PBF. That score was set to 1 when the blood flow was below 60 or above 140%. PBF between 60 and 140% was scored as 0. FEV(1 )(r = 0.648, p = 0.002) and VC (r = 0.767, p = 0.001) correlated significantly with Vdot;O(2) peak. FEV(1) (r = 0.667, p = 0.0018) correlated significantly with anaerobic threshold (AT). CT grade did not correlate with PBF mismatch score (r = 0.266, p = 0.3376). %Vdot;O(2 )peak did not correlate with CT grade (r = -0.467, p = 0.0689) or with mismatch PBF score (r = -0.327, p = 0.2377). HRCT and (99m)SPECT were advantageous for detecting the progression of disease and emphysematous changes. However, the severity of anatomical emphysematous changes did not necessarily correlate with the indices of exercise tolerance and pulmonary function tests.


The basement membrane of the enamel organ in human odontogenesis.
This study was designed to record findings of a basement membrane in human fetal jaws relative to the oral epithelium, dental lamina, and developing teeth. With the use of Lillie's allochrome stain, this could be followed from the oral epithelium and dental lamina to the tooth jaws. The basement membrane was easily traced along the inner enamel epithelium, but only after elimination of the counterstaining phases was it visible adjacent to the outer enamel epithelium.


[Purpura fulminans: functional results in two paediatric patients after suffering multiple amputations].
Purpura fulminans (PF) is an unusual haemorrhagic process that is usually associated with meningococcal sepsis and other infectious processes. It usually affects neonates and young children, and starts with a benign infection that progresses to a high fever, purpura ecchymosis, disseminated intravascular coagulopathy, necrosis and gangrene. The treatment of these children usually requires making difficult decisions, since the surgeon and the families must come to terms with the possibility of following an aggressive line of treatment that could lead to multiple mutilating sequelae, or follow palliative treatment. In this study, we review the clinical presentation, treatment and results of two cases of PF treated in our hospital between the years 2002 and 2005. The children presented in this study had a good long-term functional result and an acceptable quality of life, despite being subjected to multiple amputations.


Clear-cell hidradenoma of the forearm in a young boy.
We treated a 5-year-old boy with clear-cell hidradenoma of the forearm. Our literature search found only one previous report of this disease occurring during the first decade of life, and the present patient is the first with involvement of the limbs. This presentation demonstrates that clear-cell hidradenoma needs to be considered in the differential diagnosis of cutaneous tumors even in young children, which is of interest because malignant transformation can occur.


Anti-nociceptive effect of IL-12p40 in a rat model of neuropathic pain.
IL-12p70 is a proinflammatory cytokine secreted by dendritic cells, monocytes and macrophages. It plays a crucial role in cell-mediated immunity by inducing proliferation of T cell and natural killer cells, and enhancing their cytotoxic activity. In adaptive immune response, it acts on naive T cells to differentiate into Th1-type cells. It is composed of two subunits, p35 and p40. The latter can be secreted in the form of monodimer or heterodimer, which is also referred as IL-12p80. Recently IL-12p70 has been proven to locally provoke nociceptive effect in naïve rats. This study investigated pain response following systemic administration of IL-12p70 and IL-12p40 homodimer in chronic neuropathic pain model, induced by chronic constriction injury. The doses tested were IL-12p40 homodimer or IL12p70 at 15, 150 and 1500ng/kg, respectively. Pain was assessed at 1, 4, 7 and 24h after injection, in the form of tactile allodynia and mechanical hyperalgesia. The side effect of sensory motor disability was measured by rotarod performance. By all behavioral measures, IL-12p70 of any dosage, at any time point, had no significant effect on tactile allodynia and mechanical hyperalgesia. A high dose of IL-12p40 homodimer induced significant analgesic effect by the measure of hind paw tactile allodynia from 1h to 4h after injection. Medium and low doses of IL-12p40 homodimer exerted their analgesic effect 4h post injection. Mechanical hyperalgesia, following high and medium doses of IL-12p40 administration, was significantly reduced at 4h after application. Also, no significant sensory motor dysfunction was detected for all dosage for both homodimers. These findings suggest that systemic application of IL-12p40 homodimer induces time-dependent analgesia to mechanical stimulation in rats exposed to neuropathic pain.


ELISAs based on rNcGRA7 and rNcSAG1 antigens as an indicator of Neospora caninum activation.
Bovine abortion caused by the Apicomplexa parasite Neospora caninum is a major economical problem in the livestock industry worldwide. However, the relationship between N. caninum infection and abortion is still unknown. Our study aimed to elucidate the relationship between parasite-specific antibody responses, parasite stages and abortion. In experimentally infected cattle, anti-NcGRA7 IgG1 antibody was predominantly detected during the acute infection stage, while the production of anti-NcSAG1 IgG1 antibody was observed during both acute and chronic stages. Furthermore, levels of anti-NcGRA7 IgG2 antibody were lower than those of anti-NcSAG1 IgG2 antibody. When tested on cattle with Neospora-associated abortion, positive rates of the anti-NcGRA7 IgG2 antibody were significantly lower than those of the anti-NcSAG1 antibody, although there was no difference in IgG1 antibody-positive rates between the two antigens. In addition, anti-NcGRA7 IgG2 antibodies were not detected in cattle for more than 30days after abortion. Our results suggested that anti-NcGRA7 and anti-NcSAG1 antibodies are suitable indicators for the activation stage of N. caninum infection and broad detection of the infection, respectively. In conclusion, the use of recombinant NcGRA7 and NcSAG1-based ELISAs will be useful for evaluating the abortion risk associated with N. caninum infection.


Retention of titanium dioxide nanoparticles in biological activated carbon filters for drinking water and the impact on ammonia reduction.
Given the increasing discoveries related to the eco-toxicity of titanium dioxide (TiO2) nanoparticles (NPs) in different ecosystems and with respect to public health, it is important to understand their potential effects in drinking water treatment (DWT). The effects of TiO2 NPs on ammonia reduction, ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in biological activated carbon (BAC) filters for drinking water were investigated in static and dynamic states. In the static state, both the nitrification potential and AOB were significantly inhibited by 100 μg L(-1) TiO2 NPs after 12 h (p < 0.05), and the threshold decreased to 10 μg L(-1) with prolonged exposure (36 h, p < 0.05). However, AOA were not considerably affected in any of the tested conditions (p > 0.05). In the dynamic state, different amounts of TiO2 NP pulses were injected into three pilot-scale BAC filters. The decay of TiO2 NPs in the BAC filters was very slow. Both titanium quantification and scanning electron microscope analysis confirmed the retention of TiO2 NPs in the BAC filters after 134 days of operation. Furthermore, the TiO2 NP pulses considerably reduced the performance of ammonia reduction. This study identified the retention of TiO2 NPs in BAC filters and the negative effect on the ammonia reduction, suggesting a potential threat to DWT by TiO2 NPs.


Distribution effects on 1H double-quantum MAS NMR spectra.
The effect of a distribution in the (1)H-(1)H dipolar coupling on (1)H double-quantum (DQ) magic angle spinning (MAS) nuclear magnetic resonance (NMR) spinning sideband patterns is considered. In disordered or amorphous materials a distribution in the magnitude of the (1)H-(1)H dipolar coupling is a realistic possibility. Simulations of the (1)H DQ MAS NMR spinning sideband spectra were performed with the two-spin approximation. These simulations reveal that a dipolar coupling distribution can greatly affect the DQ spectral shape and behavior of the DQ build-up. The spectral line shapes are quantified by measurement of the relative intensities of the DQ sidebands. These variations in the (1)H DQ NMR spectra are evaluated as a function of the width of the dipolar coupling distribution. As an example, the experimental DQ spinning sideband spectrum for a hydrated polyoxoniobate containing 15 H(2)O molecules per hexaniobate cluster, are better simulated with a distribution of dipolar couplings opposed to a single coupling constant.


[Why do we require clinical guidelines for suicide prevention?]
At present, there are no German guidelines regarding suicidal behaviors in adulthood despite their relevance to public health and the well-established evidence about their prevention. This paper first describes the history and background of working with guidelines. The current status of guidelines for mental illness in Germany is presented and examined for suicide-preventive content. The need for evidence-based suicide prevention and a specific guideline for suicide prevention in adults is discussed.Only via targeted suicide prevention strategies and interventions for the respective risk groups, and by paying particular attention to age and gender specificity in the outpatient as well as inpatient sector, can a high level of care for all patients be ensured. Such strategies have to pay specific attention to the interface between the individual care sectors and need to take comprehensive, easily accessible, needs-based, and affordable sustainable medical care into account. This applies to the outpatient and inpatient sectors as well as to their interfaces. Suicidality is a cross-diagnosis syndrome that occurs in different care contexts and requires complex treatment; therefore, intersectoral and multiprofessional aspects must particularly be addressed in the guideline. Scientific evidence and interdisciplinary expert consensus on the management of suicidal behavior in medical care can help reduce morbidity and mortality associated with suicidality. In August 2021, the funding of an S3 guideline "Management of Suicidality" was approved by the Federal Joint Committee.


Neuropharmacological and Neurogenetic Correlates of Opioid Use Disorder (OUD) As a Function of Ethnicity: Relevance to Precision Addiction Medicine.
Over 100 people die daily from opioid overdose and $78.5B per year is spent on treatment efforts, however, the real societal cost is multifold greater. Alternative strategies to eradicate/manage drug misuse and addiction need consideration. The perception of opioid addiction as a social/criminal problem has evolved to evidence-based considerations of them as clinical disorders with a genetic basis. We present evaluations of the genetics of addiction with ancestryspecific risk profiles for consideration. Studies of gene variants associated with predisposition to substance use disorders (SUDs) are monolithic, and exclude many ethnic groups, especially Hispanics and African Americans. We evaluate gene polymorphisms that impact brain reward and predispose individuals to opioid addictions, with a focus on the disparity of research which includes individuals of African and Hispanic descent. PubMed and Google Scholar were searched for: Opioid Use Disorder (OUD), Genome- wide association studies (GWAS); genetic variants; polymorphisms, restriction fragment length polymorphisms (RFLP); genomics, epigenetics, race, ethnic group, ethnicity, ancestry, Caucasian/ White, African American/Black, Hispanic, Asian, addictive behaviors, reward deficiency syndrome (RDS), mutation, insertion/deletion, and promotor region. Many studies exclude non-White individuals. Studies that include diverse populations report ethnicity-specific frequencies of risk genes, with certain polymorphisms specifically associated with Caucasian and not African-American or Hispanic susceptibility to OUD or SUDs, and vice versa. To adapt precision medicine-based addiction management in a blended society, we propose that ethnicity/ancestry-informed genetic variations must be analyzed to provide real precision- guided therapeutics with the intent to attenuate this uncontrollable fatal epidemic.


Understanding the microbiota in the midst of Renaissance architecture and olive groves.
Leading scientists working on the microbiome gathered in an October 2012 meeting in Baeza, Spain, to discuss recent advances in the understanding of the role of the microbiota in immunity, pathogen colonization, metabolism and disease.


Comparative cardiac anatomy of the reptilia. III. The heart of crocodilians and an hypothesis on the completion of the interventricular septum of crocodilians and birds.
The heart of Crocodylus porosus is described, and deemed to be typical of living crocodilians after examination of the hearts of Alligator mississippiensis, Caiman crocodilus ssp., Crocodylus johnstoni and Crocodylus n. novaeguineae. Some inconsistencies between the anatomy and supposed patterns of blood flow are discussed. The crocodilian heart is compared with, and seen as an advancement of, the heart of non-crocodilian reptiles. The varanid ventricle is re-examined, as it appeared to contain many crocodilian features, along with the ophidian characteristics described previously. The broad similarities within the three groups are interpreted as adaptations towards a high pressure systemic circulation. Consequently varanids and snakes show the same left and right ventricles, as do crocodilians and birds. The evolution of the complete interventricular septum of crocodilians and birds appears to have involved three major trends: firstly, the development of a high pressure left ventricle and the fusion of most of the combined atrio-ventricular valve to the ostium of the right systemic artery; secondly, a line in which right to left shunting became gradually redundant and the vertical septum was completed to the aortico-pulmonary septum (giving rise to the avian ventricle); and thirdly, a line in which right to left shunting became increasingly important, and the vertical septum completed to the interaortic septum (giving rise to the crocodilian ventricle). Perhaps the crocodilian ancestry included a crocodile that was far more aquatic than any extant species.


Nursing evaluation and treatment of geriatric outpatients with urinary incontinence. Geriatric day hospital model: a case study.
Nurses have ideal skills to detect, assess, and treat urinary incontinence in elderly outpatients. A practical approach to promoting continence is presented. The Geriatric Day Hospital model provides an outpatient alternative for evaluating and treating frail elderly patients with multiple problems, including urinary incontinence.


Efficacy of clofazimine against acute and chronic Toxoplasma gondii infection in mice.
Toxoplasmosis is a zoonotic protozoal disease affecting approximately one-third of the world's population. The lack of current treatment options necessitates the development of drugs with good tolerance and effectiveness on the active and cystic stages of the parasite. The present study was established to investigate, for the first time, the potential potency of clofazimine (CFZ) against acute and chronic experimental toxoplasmosis. For this purpose, the type II T. gondii (Me49 strain) was used for induction acute (20 cysts in each mouse) and chronic (10 cysts in each mouse) experimental toxoplasmosis. The mice were treated with 20 mg/kg of CFZ intraperitoneally and orally. The histopathological changes, brain cyst count, total Antioxidant Capacity (TAC), malondialdehyde (MDA) assay, and the level of INF-γ were also evaluated. In the acute toxoplasmosis, both IP and oral administration of CFZ induced a significant reduction in brain parasite burden by 90.2 and 89%, respectively, and increased the survival rate to 100% compared with 60% in untreated controls. In the chronic infection, cyst burden decreased at 85.71 and 76.18% in CFZ-treated subgroups in comparison to infected untreated controls. In addition, 87.5% and 100% of CFZ-treated subgroups survived versus untreated control 62.5%. Moreover, CFZ significantly increased INF-γ levels in acute and chronic toxoplasmosis. Tissue inflammatory lesions were considerably reduced in the CFZ-treated chronic subgroups. CFZ treatment significantly reduced MDA levels and elevated TAC in both acute and chronic infections. In conclusion, CFZ showed a promising finding regarding the ability to reduce cyst burden in acute and chronic infection. Further studies are needed to investigate the therapeutic role of CFZ on toxoplasmosis using the long-term treatment and more advanced approaches. In addition, clofazimine may need to be accompanied by another drug to augment its effect and prevent the regrowth of parasites.


Composition of the aqueous phase of chromaffin granules.
Nuclear magnetic resonance spectroscopy has been used to determine the composition of the aqueous phase of bovine chromaffin granules. Relative concentrations of catecholamines (epinephrine plus norepinephrine), ATP and chromogranins have been measured from integrated intensities in the proton spectra using computer simulation techniques. Most or all of the catecholamines (97 +/- 8%) are present in the aqueous phase and contribute to the high resolution spectrum. The catecholamine:ATP molar ratio (4.41 +/- 0.45) determined by NMR is close to the value (4.45) derived from biochemical assay indicating that most or all of the ATP is present with catecholamine in the aqueous phase. Catecholamine:protein ratios show that approximately 45% of the soluble protein freed by lysis is not NMR visible. Intensity from this fraction does not appear under highly denaturing conditions (8 M urea) but reappears after hydrolysis. This behavior is similar to that of recently isolated soluble lipoprotein complexes. Variations in the NMR spectra associated with (1) different preparative procedures; (2) different suspension media, and (3) increasing osmolality are described. The fact that high concentrations of epinephrine and ATP (approximately 700 mM total) are dissolved in the aqueous phase implies that solution phase interactions at least partially ionic in nature are responsible for the low internal osmolality of chromaffin granules in vivo. Ordered phases containing a substantial fraction of the total catecholamine in an osmotically inactive form are not present.


A rare case of hemilingual abscess in a 17-year-old girl: the ease of ultrasound and the advantage of MRI.
Abscess of the tongue is rare owing to the rich vascularity and muscularity of the tongue and anti-infective properties of saliva. An abscess limited only to one half of the tongue is even more rare. We report a case of hemilingual abscess in a 17-year-old girl who presented with high-grade fever and a swollen and immobile tongue. Ultrasound (US) through floor of mouth showed inflammatory changes and collection within the right half of the genioglossus muscle. Magnetic resonance imaging (MRI) confirmed this finding, and isolated right-sided involvement was identified. US-guided aspiration of the collection yielded pus that showed gram-positive cocci on microscopy. The patient was managed conservatively, and repeat US showed resolution of the abscess. The importance of US as a quick, inexpensive, and versatile imaging technique and the precision of MRI regarding the extent of abscess of tongue are stressed.


Antifungal and Cytotoxic Evaluation of Photochemically Synthesized Heparin-Coated Gold and Silver Nanoparticles.
Heparin-based silver nanoparticles (AgHep-NPs) and gold nanoparticles (AuHep-NPs) were produced by a photochemical method using silver nitrate and chloroauric acid as metal precursors and UV light at 254 nm. UV-Vis spectroscopy graphs showed absorption for AgHep-NPs and AuHep-NPs at 420 nm and 530 nm, respectively. TEM revealed a pseudospherical morphology and a small size, corresponding to 10-25 nm for AgHep-NPs and 1.5-7.5 nm for AuHep-NPs. Their antifungal activity against Candida albicans, Issatchenkia orientalis (Candida krusei), and Candida parapsilosis was assessed by the microdilution method. We show that AgHep-NPs were effective in decreasing fungus density, whereas AuHep-NPs were not. Additionally, the viability of human gingival fibroblasts was preserved by both nanoparticle types at a level above 80%, indicating a slight cytotoxicity. These results are potentially useful for applications of the described NPs mainly in dentistry and, to a lesser extent, in other biomedical areas.


Unrelated donor stem cell transplantation in adult patients with thalassemia.
Allogeneic SCT remains the only potential cure for patients with thalassemia. However, most BMT candidates lack a suitable family donor and require an unrelated donor (UD). We evaluated whether BMT using UDs in high-risk adult thalassemia patients can offer a probability of cure comparable to that reported employing an HLA-compatible sibling as donor. A total of 27 adult thalassemia patients (15 males and 12 females, median age 22 years) underwent BMT from a UD selected by high-resolution HLA molecular typing. The conditioning regimen consisted of Busulphan (BU, 14 mg/kg) plus Cyclophosphamide (CY, 120 or 160 mg/kg) in 12 cases and BU (14 mg/kg), Thiotepa (10 mg/kg) and CY (120-160 mg/kg) in the remaining 15 cases. Cyclosporine-A and short-term Methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. In all, 19 patients (70%) are alive and transfusion-independent after a median follow-up of 43 months (range 16-137). A total of 10 patients (37%) developed grade II-IV acute GVHD and six (27%) chronic GVHD. Eight patients (30%) died from transplant-related causes. UD-BMT can cure more than two-thirds of adult thalassemia patients, and is a particularly attractive option for patients who are not compliant with conventional treatment.


Anaphylactic events observed within 4 h of ocular application of an antibiotic-containing ophthalmic preparation: 61 cats (1993-2010).
This study describes signalment, history, antibiotic administered, clinical signs observed, therapy, and outcome of anaphylactic events within 4 h following ophthalmic administration of an antibiotic to cats. Data came from survey responses (45 cats) or Federal Drug Administration reports (16 cats). Cat age (7 weeks-19 years), breed, and gender ranged widely. Most were healthy (87%) prior to anaphylaxis. Ophthalmic antibiotics commonly were administered for conjunctival (65%) or corneal (11%) disease, or ocular lubrication (7%) and contained bacitracin, neomycin, and polymyxin B (44%), or oxytetracycline and polymyxin B (21%). Polymyxin B was present in all cases. Vaccines or other drugs were also administered to 51% of cats. In 56% cases, anaphylaxis occurred within 10 min of drug application. Most (82%) cats survived. Although a causal association was not proved, ophthalmic antibiotic administration preceded anaphylaxis in all cats. Like other drugs, ophthalmic antibiotics should be used only when indicated.


Brain Dp140 alters glutamatergic transmission and social behaviour in the mdx52 mouse model of Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD) is a muscle disorder caused by DMD mutations and is characterized by neurobehavioural comorbidities due to dystrophin deficiency in the brain. The lack of Dp140, a dystrophin short isoform, is clinically associated with intellectual disability and autism spectrum disorders (ASDs), but its postnatal functional role is not well understood. To investigate synaptic function in the presence or absence of brain Dp140, we utilized two DMD mouse models, mdx23 and mdx52 mice, in which Dp140 is preserved or lacking, respectively. ASD-like behaviours were observed in pups and 8-week-old mdx52 mice lacking Dp140. Paired-pulse ratio of excitatory postsynaptic currents, glutamatergic vesicle number in basolateral amygdala neurons, and glutamatergic transmission in medial prefrontal cortex-basolateral amygdala projections were significantly reduced in mdx52 mice compared to those in wild-type and mdx23 mice. ASD-like behaviour and electrophysiological findings in mdx52 mice were ameliorated by restoration of Dp140 following intra-cerebroventricular injection of antisense oligonucleotide drug-induced exon 53 skipping or intra-basolateral amygdala administration of Dp140 mRNA-based drug. Our results implicate Dp140 in ASD-like behaviour via altered glutamatergic transmission in the basolateral amygdala of mdx52 mice.


Defect in cholesterol esterification associated with renal diseases.
Changes in lipidaemia and in cholesterol esterification rate were investigated in 65 patients with chronic mesangial glomerulonephritis (GN), and in 26 patients with polycystic kidneys (PL), as well as in age- and sex-matched control groups. As compared to the controls, a slightly significant increase in cholesterol and triglyceride concentrations was found only for the GN group, whereas the rate of cholesterol esterification showed a highly significant reduction in both groups of diseased subjects. The average values of molar esterification rate (MER) were, respectively, 75.4 and 61.6 mumol . l-1 . h-1 for the GN and PL groups, the respective control values being 96.9 and 91.1. Fractional esterification rate (FER) reflecting the rate of cholesterol exchange between blood and tissues fell in the same two groups of patients to 4.38 and 4.40% . h-1, respectively (controls 6.93 and 6.17). Both the changes in cholesterol esterification rates and a relative increase in the ratio of unesterified to esterified cholesterol were found in patients with low as well as normal glomerular filtration rates.


Symmetry of effector function in the immune system network.
Symmetry in antibody plus complement mediated killing between a T15 idiotype-bearing monoclonal antibody (HPC-M2) and an anti-T15 monoclonal antibody (B36-82) is demonstrated. The HPC-M2 antibody is also shown to be multispecific in its effector function, since it lyses both phosphorylcholine coated erythrocytes, and B36-82 Fab coated red blood cells. The symmetry and multispecificity in effector function are presented as new evidence against the concept that the paratope of antibody molecule exists as a uniquely defined site on the antibody variable region. A theoretical consequence for immune system network theory is that the anti-idiotypic set and the internal image are functionally equivalent, the results support symmetric network models of regulation, and are evidence against asymmetric models.


Gene variants in pro-coagulant and anti-coagulant genes could be prognostic genetic markers of COVID-19 susceptibility.
Present study aimed to identify DNA polymorphisms (variants) which can modulate the risk of COVID-19 infection progression to severe condition. TaqMan based SNP genotyping assay was performed for 11 single nucleotide polymorphisms (SNPs) in pro-coagulant and anti-coagulant genes. A total of 33 COVID-19 patients, including dead, severe and moderately infected individuals were compared to 35 healthy controls. Both alleles in the SNP were labelled with two different fluorescent dyes (FAM and VIC) during assay formulation. DNA of study subjects were mixed with SNP assay and TaqMan master mix on 96 well PCR plate according to manufacturer's protocol and RT-PCR was performed. Allelic discrimination assay gave clear results for presence of specific allele in each sample. Three SNPs were located in the pro-coagulant genes, another three involved in blood clot dissolution while rest five were in the genes encoding natural anti-coagulants. COVID-19 infected patients were further sub-divided into three groups, deceased (n = 16), severe (n = 10) and moderately infected (n = 7). SNP genotyping showed significant differences between COVID-19 patients and controls in two SNPs, rs6133 in Selectin-P (SELP) and rs5361 in Selectin-E (SELE) gene. Also, rs2020921 and rs8176592, in clot dissolution genes, tissue Plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) respectively showed significant genotypic and allelic difference in patients of COVID-19 compared to healthy controls. Further three SNPs rs2227589, rs757583846, and rs121918476 in natural anti-coagulant genes anti-thrombin III (ATIII), protein C (PROC), and protein S (PROS) respectively showed statistically significant difference between the study groups. Our findings indicate that gene variants, those involved in coagulation and anti-coagulation may play a major role in determining individual susceptibility to COVID-19.


Roles of auxin response factors in rice development and stress responses.
Auxin signalling plays a key role in various developmental processes ranging from embryogenesis to senescence in plants. Auxin response factor (ARF), a key component of auxin signalling, functions by binding to auxin response element within promoter of auxin response genes, activating or repressing the target genes. Increasing evidences show that ARFs are crucial for plant response to stresses. This review summarises the recent advance on the functions and their regulatory pathways of rice ARFs in development and responding to stresses. The importance of OsARFs is demonstrated by their roles in triggering various physiological, biochemical and molecular reactions to resist adverse environmental conditions. We also describe the transcriptional and post-transcriptional regulation of OsARFs, and discuss the major challenges in this area.


Sustainable sorption strategies for removing Cr(3+) from tannery process wastewater.
Two different strategies for the removal of trivalent chromium (Cr(3+)) from contaminated water are reported. The first one is based on the sorption process on an organo-mineral complex, named LDH-HP, obtained in turn by sorption of polymerin, the humic acid-like fraction occurring in olive oil mill wastewater, on a layered double hydroxide (LDH) of magnesium and aluminium with carbonate in the interlayer. This sorption process is preliminary developed on simulated wastewater (SW) as theoretical model and successively applied on tannery process wastewaters (TPWs) natively containing Cr(3+). The removal of Cr(3+) from TPW is lower than that observed for SW, because of the large compositional variability of TPW. The second one is based on the direct production of a LDH of magnesium and chromium (Cr(3+)), using as starting material TPW, naming LDH-TPW the complex produced. This process allows the complete removal of Cr(3+) from TPW and also the abatement of chemical oxygen demand, indicating to be a very promising purification process for an industrial application.


The value of DTI: achieving high diagnostic performance for brain metastasis.
The evaluation of brain metastases generally requires post-contrast MRI exam, but some patients have contraindication to contrast medium administration. To investigate the value of the MRI diffusion tensor imaging (DTI) for detection of metastatic brain tumor. We retrospectively analyzed the MRI data from 23 patients (13 males and 10 females) with brain metastases. The MRI protocol consisted in T1WI, T2WI, post-contrast 3DT1WI and DTI images (b = 1000) sequences. The brain metastatic lesions were counted in each of these sequences. We compared the advantages and limitations of different sequences in the brain metastases detection. The number of metastatic lesions identified on the contrast-enhanced 3DT1WI image is used as the reference. FA values were measured in the intratumoral, adjacent peritumoral and distant peritumoral edema area (PTEA) of brain metastasis, and the differences were statistically analyzed. DTI can detect more brain metastatic lesions rather than T1WI and T2WI. The number of brain metastases on DTI is similar to post-contrast 3D T1WI. There is no statistical difference in the FA value change between the adjacent and distant PTEA. The DTI original image can be used as an alternative examination for patients with contraindications to contrast-enhanced MRI. It has high sensitivity to intratumoral hemorrhage, which has advantage to detect brain metastatic lesions as compared with T1WI or T2WI images.


Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice.
Clinical trials are currently testing whether induction of haploidentical mixed chimerism (Haplo-MC) induces organ transplantation tolerance. Whether Haplo-MC can be used to treat established autoimmune diseases remains unknown. Here, we show that established autoimmunity in euthymic and adult-thymectomized NOD (H-2g7) mice was cured by induction of Haplo-MC under a non-myeloablative anti-thymocyte globulin-based conditioning regimen and infusion of CD4+ T cell-depleted hematopoietic graft from H-2b/g7 F1 donors that expressed autoimmune-resistant H-2b or from H-2s/g7 F1 donors that expressed autoimmune-susceptible H-2s. The cure was associated with enhanced thymic negative selection, increased thymic Treg (tTreg) production, and anergy or exhaustion of residual host-type autoreactive T cells in the periphery. The peripheral tolerance was accompanied by expansion of donor- and host-type CD62L-Helios+ tTregs as well as host-type Helios-Nrp1+ peripheral Tregs (pTregs) and PD-L1hi plasmacytoid DCs (pDCs). Depletion of donor- or host-type Tregs led to reduction of host-type PD-L1hi pDCs and recurrence of autoimmunity, whereas PD-L1 deficiency in host-type DCs led to reduction of host-type pDCs and Helios-Nrp1+ pTregs. Thus, induction of Haplo-MC reestablished both central and peripheral tolerance through mechanisms that depend on allo-MHC+ donor-type DCs, PD-L1hi host-type DCs, and the generation and persistence of donor- and host-type tTregs and pTregs.