Induced resistance to rice sheath blight (Rhizoctonia solani Kühn) by β-amino-butyric acid conjugate of phenazine-1-carboxylic acid.
Rice sheath blight caused by Rhizoctonia solani Kühn is a major fungal disease that plagues commercially grown rice. Occurring mainly in leaf sheaths and leaves, the disease leads to great losses in food production. β-amino-butyric acid (BABA) has been demonstrated to activate an induced resistance response and is a potent inducer of broad-spectrum disease resistance in different plant species. In this study, β-amino-butyric acid conjugate of phenazine-1-carboxylic acid (PCA) with prominent induced resistance to rice sheath blight was tested. The in vitro fungicidal activity, as well as in vivo efficacy, systemicity, induced resistance and defense enzyme activity of BABA conjugate of PCA against R. solani in rice seedlings was systematically evaluated. The results indicated that in vitro fungicidal activity of PCA-β-aminobutyric acid (4e) against R. solani was lower than that of PCA, but in vivo curative ability of 4e was the highest among all tested compounds. The systemicity tests in rice seedlings revealed that PCA did not possess phloem mobility, while 4e exhibited moderate phloem mobility but much lower thanα-amino-butyric acid conjugate of PCA (4d). In addition, Compound 4e showed the highest induced activity against rice sheath blight. The observed effects of defense enzymes help to explain this high level of induced activity. The current research results indicate that in rice seedlings, BABA conjugate of PCA induce observable resistance to rice sheath blight and exhibit moderate phloem mobility, which could be used as an induced resistance fungicide against rice sheath blight in commercial rice production. The BABA conjugate of PCA might provide a useful example of induced resistance to R. solani.


State Size and Government Level Matter Most: A Structural Equation Model of Local Health Department Policy Behaviors.
To explore relationships between local health department policy behaviors, levels of government activity, policy focus areas, and selected health department characteristics. Cross-sectional analysis of secondary data from the 2013 National Association of County & City Health Officials (NACCHO) Profile Survey. Local health departments throughout the United States. A total of 2000 local health departments responding to the 2013 Profile Survey of Local Health Departments. Survey data were gathered by the NACCHO. Secondary analysis of reported policy behaviors for the 2013 NACCHO Profile Survey. A structural equation model tested effects on and between state population size, rurality, census region and policy focus, and the latent variables of policy behavior formed from a confirmatory factor analysis. Policy behaviors, levels of government activity (local, state, and federal), policy focus areas, and selected local health department characteristics. The majority (85.1%) of health departments reported at least one of the possible policy behaviors. State population size increased the probability of local policy behavior, and local behavior increased the probability of state policy behavior. State size increased the likelihood of federal policy behavior and the focus on tobacco, emergency preparedness, and obesity/chronic disease. However, the more rural a state was, the more likely policy behavior was at the state and federal levels and not at local levels. Specific policy behaviors mattered less than the level of government activity. Size of state and rurality of health departments influence the government level of policy behavior.


Homeostatic model assessment (HOMA) index cut-off values to identify the metabolic syndrome in children.
The aim of the study was to establish the best cut-off value for the homeostatic model assessment (HOMA) index in identifying children and adolescents with the metabolic syndrome. The study included 72 non-obese and 68 obese children aged 7 to 16 years. Obesity is defined using the criteria proposed by Cole et al., being included as metabolic syndrome variables waist circumference, systolic blood pressure, diastolic blood pressure and seric values of glucose, uric acid, fasting insulin, leptin, triglycerides and HDL-cholesterol. Children were considered as having the metabolic syndrome when four or more characteristics showed abnormal values. The HOMA index was calculated as the product of the fasting plasma insulin level (microU/mL) and the fasting plasma glucose level (mmol/L), divided by 22.5. HOMA index cut-offs from the 5th to the 95th percentile were used. A receiver operating characteristic (ROC) curve was generated using the different HOMA cut-offs for the screening of the metabolic syndrome. The areas under the ROC curve, 95% confidence intervals, and the point to the ROC curve closest to 1, were calculated. The area under the ROC curve was 0.863 (95% C.I.: 0.797, 0.930). The point closest to 1 corresponds to the 60th percentile of the HOMA index distribution in our sample. HOMA index value at the 60th percentile was 2.28. Cut-off values corresponding to a range of HOMA index from the 50 to the 75 percentile, showed similar distances to 1. HOMA index values for percentiles 50 to 75 ranged from 2.07 to 2.83. In conclusion, HOMA index could be a useful tool to detect children and adolescents with the metabolic syndrome. HOMA cut-off values need to be defined in the paediatric population; however, values near to 3 seem to be adequate.


Preventing sexism and sexual harassment in medical schools by using Theater of the Oppressed as an interactive and reflexive tool.
Among the measures taken to combat sexism and sexual harassment, prevention courses for medical students are one possibility. We aimed to describe the process of implementing a training course on the prevention of sexism and sexual harassment for medical students in two Swiss medical schools by using the Theater of the Oppressed as an interactive and reflexive tool within the course. The purpose of this theater was to give the students the opportunity to express themselves and to collectively look for and discuss ways to combat and escape from oppressive situations. This collaborative, innovative, and interactive implementation showed that different forms of a training course can be implemented with similar objectives in an adaptable and transferable manner. The interactive and reflexive Theater of the Oppressed was an appropriate option to reach the objectives. Courses were based on identifying and acting on concrete problematic situations by focusing on individual, collective, and institutional resources. Students reported a high level of satisfaction.


A phase 1 study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of simvastatin with topotecan and cyclophosphamide in children with relapsed/refractory solid and central nervous system (CNS) tumors. Simvastatin was administered orally twice daily on days 1-21, with topotecan and cyclophosphamide intravenously on days 1-5 of a 21-day cycle. Four simvastatin dose levels (DLs) were planned, 140 (DL1), 180 (DL2), 225 (DL3), 290 (DL4) mg/m2 /dose, with a de-escalation DL of 100 mg/m2 /dose (DL0) if needed. Pharmacokinetic and pharmacodynamic analyses were performed during cycle 1. The median age of 14 eligible patients was 11.5 years (range: 1-23). The most common diagnoses were neuroblastoma (N = 4) and Ewing sarcoma (N = 3). Eleven dose-limiting toxicity (DLT)-evaluable patients received a median of four cycles (range: 1-6). There were three cycle 1 DLTs: one each grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) elevations at DL1, and one grade 4 CPK elevation at DL0. All patients experienced at least one grade 3/4 hematologic toxicity. Best overall response was partial response in one patient with Ewing sarcoma (DL0) and stable disease for four or more cycles in four patients. Simvastatin exposure increased with higher doses and may have correlated with toxicity. Plasma interleukin 6 (IL-6) concentrations (N = 6) showed sustained IL-6 reductions with decrease to normal values by day 21 in all patients, indicating potential on-target effects. The MTD of simvastatin with topotecan and cyclophosphamide was determined to be 100 mg/m2 /dose.


Otitis media with effusion: academic attainment and socioeconomic background.
In a recent paper (Brooks, D.N., Otitis media with effusion and academic attainment, Int. J. Pediat. Otorhinolaryngol., 12 (1986) 39-47) the relationship between severity of otitis media with effusion (O.M.E.) in childhood and eventual outcome was explored in a group of 64 individuals. Although the severity of O.M.E. was related to time loss from education through sickness during the first school years, no effect on academic attainment levels was found. Further data have been obtained on the socio-economic groupings (S.E.G.) of 59 of the children. No correlation was found between S.E.G. and either time lost from school through sickness or severity of O.M.E. A strong correlation was found between S.E.G. and eventual academic attainment level.


Recent evidence of animal exploitation in the Axumite epoch, 1st-5th centuries AD.
This study reports evidence of animal exploitation during the Axumite era based on a survey of architectural features, rock art and artefacts recovered from the archaeological site at Axum, northern Ethiopia. Animals and agricultural tools were identified from materials not previously examined. Pottery, rock art and animal remains revealed a range of zoological species. Agricultural implements and sacrificial vessels also provided indirect evidence of animal exploitation. It is concluded that, in addition to plough-based agriculture, the hunting of large wild animals, such as elephants and lions, and the exploitation of domestic cattle, small ruminants and poultry were part of the Axumite subsistence regime. Although it is difficult to reconstruct an overall subsistence pattern based on this study alone, the physical and biological evidence suggests that the Axumites practised combined cultivation and animal herding. Further investigation is required to study the types and breeds of animals and their distribution in time and space.


Anti-tumor potential of nitroxyl derivative Pirolin in the DMBA-induced rat mammary carcinoma model: A comparison with quercetin.
Considering the role of oxidative stress in carcinogenesis, we investigated the effect of synthetic antioxidant Pirolin (3-carbamoyl-2,2,5,5-tetramethylpyrroline-1-oxyl) on breast cancer progression. Since the anticancer drugs may cause cardiotoxicity due to oxidative stress in the heart muscle, we also evaluated Pirolin performance in heart tissue and compared its effect with that of the natural dietary flavonoid quercetin. Sprague-Dawley rats were administered with 7,12-dimethylbenz(a)anthracene (DMBA) and then treated ip with an antioxidant (each at a dose of 10mg/kg b.w.) for 14 days. The histopathology of tumors, their size and multiplicity were assesed. The effect of antioxidants on heart tissue was evaluated by the oxidative stress markers and poly (ADP-ribose) polymerase 1 (PARP 1) cleavage. The median number of tumors and their volume, at the end of the study, were considerably smaller in both antioxidant-treated groups. We found a better antioxidative performance of quercetin in the heart, since a restoration of the GSH pool and decreased amount of hydroperoxides were observed. Antioxidants did not prevent cardiomyocytes from apoptosis. The attenuation of tumor progression by Pirolin was comparable with the action of quercetin. No negative changes were observed in the heart of animals after Pirolin treatment. Thus, its use in targeting deregulated redox pathways should be further studied.


A case of polyomavirus-associated nephropathy presenting late after transplantation.
A 36-year-old white female, who had received a deceased-donor kidney transplant for end-stage renal disease secondary to reflux nephropathy 8 years previously, was referred to a transplant clinic for evaluation following an increase in her serum creatinine level from 123.8 micromol/l to 185.6 micromol/l (1.4 mg/dl to 2.1 mg/dl) over the preceding 9 months. Her immunosuppression regimen included mycophenolate mofetil, ciclosporin and prednisone, with ciclosporin trough levels ranging from 100 ng/ml to 150 ng/ml, as detected by fluorescence polarization immunoassay, over the preceding year. The following possible causes of subacute renal failure were ruled out: post-obstructive nephropathy, altered hemodynamics (hypotension and renal artery stenosis), and toxicity from medications other than calcineurin inhibitors. Potential etiologies such as acute T-cell-mediated rejection, acute and chronic antibody-mediated rejection, polyomavirus-associated nephropathy, and calcineurin inhibitor nephrotoxicity were considered. Physical examination, urine and blood analysis, analysis of human leukocyte antigen antibodies by flow cytometry (Luminex, Luminex Corporation, Austin, TX), ultrasound of the transplanted kidney, polymerase chain reaction assay for the detection of BK virus in the serum, and biopsy of the transplanted kidney with staining for simian virus 40 antigen. Polyomavirus-associated nephropathy with advanced nephrosclerosis and moderate to marked hyaline arteriolosclerosis. Reduction of immunosuppression by discontinuation of mycophenolate mofetil, dose reduction of ciclosporin, and initiation of leflunomide.


Eating Disorders and Associated Health Risks Among University Students.
To determine the prevalence of eating disorders among university students and its relationship to behavioral characteristics and substance use. Cross-sectional study collected socioeconomic characteristics and behavioral risk. University of Upper Normandy, France. University student volunteers. The Sick, Control, One stone, Fat, Food (SCOFF) screening test was used to identify subjects with eating disorders by a confidential questionnaire self-administered either online or on paper. Multivariate logistic regression models with P < .05 considered significant. A total of 3,457 students were included with a male-to-female ratio of 0.57. The prevalence of positive SCOFF screening was 20.5% among students. A positive relation between the positive SCOFF was observed with female gender (adjusted odds ratio [AOR], 2.98; 95% confidence interval [CI], 2.28-3.89; P < .001), stress (AOR, 1.10; 95% CI, 1.09-1.12; P < .001), depression (AOR, 8.62; 95% CI, 3.37-22.10; P < .001) alcohol abuse problems (AOR, 1.52; 95% CI, 1.20-1.95; P = .006), and risk of cyber-addiction (AOR, 5.09; 95% CI, 2.69-9.62; P < .001). Eating disorders are highly prevalent among university students in France and associated with other behavior risks, stress, and depression. It might prove necessary in the future to screen students with the SCOFF questionnaire upon entry to the university to inform student about the risk of eating disorders and advise them to consult with their general practitioner.


Mice varying in resistance to African trypanosomiasis respond differently to treatments with variant surface glycoprotein.
A comparative analysis of responses between resistant and susceptible hosts revealed that DBA/2 mice, after treatment with variant surface coat glycoprotein (VSG) from virulent or avirulent African trypanosomes, developed splenomegaly as the result of a near-doubling of the splenic cell population, had less polyclonal activation of B cells and were protected upon challenge with homologous trypanosomes. The susceptible C3H/Anf and C3H/HeJ mice on the other hand increased their splenic cell population by only 12%, had about twice the production of unelicited antibodies and were not immunized by the VSG treatments. This indicated that (a) proliferation of spleen cells during African trypanosomiasis may reflect an attempt to generate a specific and protective immune response and is not merely the result of polyclonal activation of lymphocytes; (b) production of unelicited antibodies is not merely a "bystander reaction" to the generation of antigen-specific responses; and (c) polyclonal antibody production in response to VSG is not linked to the LPS gene. Nonspecific immunosuppression as measured in mitogen assays was not elicited by VSG in either resistant or susceptible mice, indicating that polyclonal lymphocyte activation and nonspecific immunosuppression are unlinked phenomena. Mice injected with VSG from either virulent or avirulent isolates at levels normally encountered by hosts during severe, acute infection developed the same degree of splenomegaly and production of unelicited (polyclonal) antibodies. Therefore, any differences in polyclonal activation of lymphocytes measured between mice with acute vs. chronic African trypanosomiasis can be attributed to quantitative and not qualitative differences in VSG.


Giant uterine mass with uterine smooth muscle tumor of uncertain malignant potential: A case report.
Uterine smooth muscle tumor of uncertain malignant potential (STUMP) is a rare tumor belonging to a group of smooth muscle tumors that possess both benign and malignant features, complicating the diagnosis.Case report.We present the case of a 41-year-old primiparous woman who complained of heavy menstrual bleeding and severe pressure symptoms in the lower abdomen for 3 months. Magnetic resonance imaging revealed a large intramural myoma measuring 35 × 25 cm in the lower uterine corpus. A laparotomy including total hysterectomy was performed. Grossly, the uterine mass measured 38.5 × 35.4 × 20.4 cm in the largest diameter and weighed 18.3 kg. Pathological analysis revealed a uterine mass diagnosed as a smooth muscle tumor of uncertain malignant potential. The patient was normally discharged 7 days after surgery and decided to follow up without further treatment. At the time of this report, the patient had been followed up as an outpatient for 18 months without recurrence. Giant uterine STUMP is extremely rare and difficult to diagnose on physical examination and imaging findings alone. It is important to consider the possibility of an underlying malignancy when performing a preoperative examination and to perform frozen biopsy if malignancy is suspected. During follow-up, patients should undergo consultation with a gynecologic oncologist and should be surveilled closely because of the possibility of recurrence or metastasis.


Single-Cell Analysis: The Differences That Kill.
Using single-cell RNA sequencing, Avraham et al. investigate how variability in macrophage response to infection is controlled by variability within the pathogen population. They find that heterogeneous expression of the Salmonella virulence factor PhoP and subsequent cell-wall modifications lead to the bimodal induction of the interferon-response in infected macrophages.


Anterior segment OCT-based diagnosis and management of retained Descemet's membrane following penetrating keratoplasty.
To report a case of retained Descemet's membrane after penetrating keratoplasty for congenital hereditary endothelial dystrophy (CHED) documented by anterior segment optical coherence tomography and review of literature. Case report and review of literature. A 14-year-old boy underwent penetrating keratoplasty for CHED. A retained host Descemet's membrane was detected with a supernumerary anterior chamber on the first postoperative day. The retained Descemet's membrane was documented using slit lamp adapted anterior segment optical coherence tomography (SLOCT). Surgical intervention for the Descemet's membrane removal was done in the third postoperative week. The complete removal of the membrane was confirmed on SLOCT. Inadvertent retention of the host Descemet's membrane is a rare but possible complication in penetrating keratoplasty for CHED. Proper anticipation, early detection and removal will help in preventing any undue risk of graft failure.


The effect of L-3, 4-dehydroproline on the antitumor activity and toxicity of bleomycin.
Pulmonary fibrosis is a serious side effect that limits the therapeutic utility of bleomycin (BLM). Recently, it has been demonstrated that L-3, 4-dehydroproline (DHP), a proline analog, significantly reduced the extent of pulmonary fibrosis in rats administered BLM intratracheally. The present studies were performed to determine the effect of DHP on the oncolytic and toxicologic effects of BLM. DHP (25 mg/kg/day) administered sc concomitantly with BLM (4 mg/kg/day) for 9 consecutive days following a sc inoculation of B16 melanoma cells in BDF1 had no effect on tumor growth inhibition by BLM when tumor growth rate was assessed by tumor volume and by tumor weight. To determine the effect of DHP on the toxicity of BLM, DHP (25 mg/kg/day) and BLM (10 mg/kg/day) were administered to Sprague-Dawley rats for 5 consecutive days followed by 2 days of rest and 5 additional days of drug administration. BLM administration produced decreased body weight gain, acute leukocytopenia, delayed elevation in blood nitrogen levels, chronic lung and kidney disease, and alopecia. Animals administered BLM plus DHP had a similar toxicologic profile. One striking difference was that no animal administered BLM plus DHP developed alopecia, whereas five of eight rats administered BLM alone displayed this untoward effect. These results suggest that DHP neither diminishes the oncolytic activity nor exacerbates the nonpulmonary toxicity of BLM, DHP would appear, therefore, to be a potential candidate as an antifibrotic adjunct to BLM therapy.


Oral versus intravenous palonosetron in Chinese cancer patients receiving moderately emetogenic chemotherapy: A non-inferiority phase III trial.
The 5-hydroxytryptamine-3 receptor antagonist palonosetron (PALO) is approved (United States/Europe) as an oral formulation for prevention of chemotherapy-induced nausea and vomiting in adult cancer patients undergoing moderately emetogenic chemotherapy (MEC) for the acute phase only, in the United States, or as intravenous (IV) formulation in patients undergoing MEC or highly emetogenic chemotherapy. This phase III study compares the efficacy/safety of oral versus IV PALO in Chinese patients. Chemotherapy-naive patients with solid tumours scheduled for MEC received oral PALO 0.50 mg or IV PALO 0.25 mg. The primary objective was to demonstrate non-inferiority in terms of patients with complete response in the acute phase (0-24 hr post-chemotherapy). Complete response rates (acute phase), evaluated in 318/320 randomised patients, were 84.6% and 85.9% for oral and IV PALO respectively. Non-inferiority was demonstrated; the two formulations showed similar efficacy/safety. Non-inferiority of oral versus IV PALO in the acute phase was demonstrated in Chinese patients. CTR20140711.


Targeting c-Met in Cancer by MicroRNAs: Potential Therapeutic Applications in Hepatocellular Carcinoma.
Preclinical Research Cancer is one of the world's deadliest diseases, with very low survival rates and increased occurrence in the future. Successfully developed target-based therapies have significantly changed cancer treatment. However, primary and/or acquired resistance in the tumor is a major challenge in current therapies and novel combinational therapies are required. RNA interference-mediated gene inactivation, alone or in combination with other current therapies, provides novel promising therapeutics that can improve cure rate and overcome resistance mechanisms to conventional therapeutics. Hepatocyte Growth Factor/c-Met signaling is one of the most frequently dysregulated pathways in human cancers and abnormal c-Met activation is correlated with poor clinical outcomes and drug resistance in hepatocellular carcinoma (HCC). In recent years, a growing number of studies have identified several inhibitors and microRNAs (miRNAs), specifically targeting c-Met in various cancers, including HCC. In this review, we discuss current knowledge regarding miRNAs, focusing on their involvement in cancer and their potential as research tools and therapeutics. Then, we focus on the potential use of c-Met targeting miRNAs for suppressing aberrant c-Met signaling in HCC treatment.


Electrochemical detection of dopamine using arrays of liquid-liquid micro-interfaces created within micromachined silicon membranes.
The detection of protonated dopamine by differential pulse voltammetry (DPV) and square wave voltammetry (SWV) at arrays of micro-interfaces between two immiscible electrolyte solutions (microITIES) is presented. Microfabricated porous silicon membranes (consisting of eight pores, 26.6 microm in radius and 500 microm pore-pore separation, in a hexagonal layout) were prepared by photolithographic and etching procedures. The membrane pores were fabricated with hydrophobic internal walls so that the organic phase filled the pores and created the liquid interface at the aqueous side of the membrane. These were used for harnessing the benefits of three-dimensional diffusion to the interface and for interface stabilisation. The liquid-liquid interface provides a simple method to overcome the major problem in the voltammetric detection of dopamine at solid electrodes due to the co-existence of ascorbate at higher concentrations. Selectivity for dopamine over ascorbate was achieved by the use of dibenzo-18-crown-6 (DB18C6) for the facilitated ion transfer of dopamine across the microITIES array. Under these conditions, the presence of ascorbate in excess did not interfere in the detection of dopamine and the lowest concentration detectable was ca. 0.5 microM. In addition, the drawback of current signal saturation (non-linear increase of the peak current with the concentration of dopamine) observed at conventional (millimetre-sized) liquid-liquid interfaces was overcome using the microfabricated porous membranes.


[Severe hypokalemia with paralysis in a patient with distal renal tubular acidosis as an initial expression of Sjögren's syndrome].
In a 33-year-old woman with a recent flaccid paralysis of the arms and legs, laboratory tests demonstrated a severe hypokalemia with hyperchloremic metabolic acidosis and abnormally acidified urine. The urinary anion gap was positive in the presence of acidosis, thus establishing the diagnosis of distal renal tubular acidosis. The patient made a full recovery after potassium and alkali replacement. Further investigation revealed Sjögren's syndrome as the underlying cause.


[Problems of tracheotomy in locally invasive anaplastic thyroid cancer].
Between 1955-1985 515 patients with carcinoma of the thyroid have been operated. Among 170 cases with a local infiltration 69 tracheostomies were performed in 55% for lesions of both laryngeal nerves or intratracheal bleeding (absolute indication), in 45% as a prophylactic intraoperative procedure to avoid later death from asphyxiation (relative indication). In a retrospective study clinical results were analysed with special reference to the question whether patients profit by the tracheostomy. Follow-up examinations showed that tracheostomy did not influence the outcome of patients with a differentiated thyroid carcinoma while there was a remarkable difference in survival of patients with anaplastic tumors where those with a tracheostomy had a worse survival. In this group postoperative external radiotherapy often could not be administered or was delayed due to local complications of the tracheostoma.


The beginnings of the debate between the Mendelians and the Biometricians in psychiatric genetics: David Heron, Karl Pearson, Abraham Rosanoff, and Charles Davenport 1913-1914.
The world learned of the heated dispute about the methodology of the early works by Davenport and Rosanoff claiming Mendelian transmission patterns for mental handicap and psychiatric illness in a bold headline in the New York Times on Sunday, November 9, 1913: ENGLISH EXPERT ATTACKS AMERICAN EUGENIC WORK. I here focus on the debate surrounding Rosanoff's 1911 study where he presented evidence that the neuropathic constitution, including, among its manifestations, dementia praecox, and manic-depressive illness, was an autosomal recessive trait. The "English expert," David Heron, a student of Pearson's, launched the debate in his 1913 paper which argued that Rosanoff's field work methods were biased, his clinical assessments sloppy, his phenotype far too broad, and his statistical approach flawed. Both Davenport, Rosanoff's mentor, and Rosanoff vigorously defended their methods. Behind this sometimes personal debate was the long simmering controversy about the relative validity of Biometrical genetic (represented by Heron and Pearson) and Mendelian genetic (represented by Rosanoff and Davenport) models for genetic transmission in plants, animals and, especially, humans. A review suggests that most of Heron's criticisms were valid. This episode presages later controversies within psychiatric genetics, for example between twin and linkage researchers in the 1980s and 1990s.


Male and female C57BL/6 mice display drug-induced aversion and reward in the combined conditioned taste avoidance/conditioned place preference procedure.
Drugs of abuse have rewarding and aversive effects that, in balance, impact abuse potential. Although such effects are generally examined in independent assays (e.g., CPP and CTA, respectively), a number of studies have examined these effects concurrently in rats in a combined CTA/CPP design. The present study assessed if similar effects can be produced in mice which would allow for determining how each is affected by subject and experiential factors relevant to drug use and abuse and the relationship between these affective properties. Male and female C57BL/6 mice were exposed to a novel saccharin solution, injected (IP) with saline or 5.6, 10 or 18 mg/kg of the synthetic cathinone, methylone, and placed on one side of the place conditioning apparatus. The following day, they were injected with saline, given access to water and placed on the other side of the apparatus. After four conditioning cycles, saccharin avoidance and place preferences were assessed in a final two-bottle CTA test and a CPP Post-Test, respectively. In the combined CTA/CPP design, mice acquired a significant dose-dependent CTA (p = 0.003) and a significant CPP (p = 0.002). These effects were independent of sex (all ps > 0.05). Further, there was no significant relationship between the degree of taste avoidance and place preference (p > 0.05). Similar to rats, mice displayed significant CTA and CPP in the combined design. It will be important to extend this design in mice to other drugs and to examine the impact of different subject and experiential factors on these effects to facilitate predictions of abuse liability.


Phase II trial of recombinant leukocyte A interferon in advanced malignant melanoma.
A total of 21 patients with advanced metastatic malignant melanoma were treated in this efficacy study of recombinant leukocyte A interferon (interferon alpha-2a). Patients received 18 X 10(6) units interferon alpha-2a by i.m. injection daily for the first 10 weeks and then three times weekly for a further 4 months. The symptoms of toxicity observed in this study resembled those previously reported for alpha interferons and included fever, chills, fatigue, anorexia, myalgia, headache, occasional nausea and vomiting, dose-dependent reversible leukopenia, and hepatic transaminase elevations. Of the 21 patients, 12 had evidence of tumor progression, 6 had stable disease for at least 2 months, and complete remission was seen in 3 patients with stage III melanoma. We conclude that interferon alpha-2a appears to have some antiproliferative effect in metastatic malignant melanoma. While its use in stage IV patients with big tumor masses is doubtful, there seems to be therapeutic benefit in earlier stages.


Laparoscopy in the management of scirrhous gastric cancer.
BACKGROUND: Scirrhous gastric cancer frequently shows extensive tumor spread, and gastrectomy for cure of the disease is not possible in the presence of peritoneal dissemination, which is often overlooked by conventional computed tomography. The aim of this study was to evaluate our experience of 16 patients who underwent laparoscopy in the management of scirrhous gastric cancer, and to examine whether peritoneal dissemination could be diagnosed accurately by laparoscopy.METHODS: All patients had nonobstructed, nonbleeding scirrhous gastric cancer and had no evidence of metastatic disease by ultrasonography and computed tomography. Laparoscopy was performed under general anesthesia with CO(2) pneumoperitoneum. A Hasson trocar and two manipulating forceps were inserted, and the surfaces of the peritoneum, omentum, stomach, spleen, pancreas, liver, and diaphragm were examined.RESULTS: The mean time for laparoscopy was 20 min. Peritoneal dissemination was disclosed in 4 patients (25%), and systemic and intraperitoneal chemotherapy was done without laparotomy. In 12 patients, subsequent gastrectomy with a curative intent was successfully performed. Pathology revealed that the tumor diffusely invaded the whole thickness of the gastric wall; the mean size of resected tumors was 12 cm, and the mean number of positive nodes was 17. Nine patients died of the disease with a mean survival period of 10 months, and 7 patients were alive without recurrence during a mean follow-up period of 11 months.CONCLUSIONS: Laparoscopy is useful for the evaluation of peritoneal spreads of advanced gastric cancer, can avoid unnecessary laparotomy because of peritoneal dissemination, and is important for the choice of treatments in patients with scirrhous gastric cancer.


The association of pathogenic factors of metabolic syndrome on serum prostate-specific antigen levels: a pilot study.
Metabolic syndrome (MetS) and serum prostate-specific antigen (PSA) levels are correlated. To investigate the underlying effect of MetS on PSA levels, the relationship between the major pathogenic factors of MetS and serum PSA levels was studied. A total of 506 ostensibly healthy men who underwent routine health check-ups were recruited to this study. We evaluated the effect of the major pathogenic factors of MetS, which included insulin resistance, a subclinical inflammatory state and sexual hormone changes, on serum PSA levels by using linear regression analysis and multivariate analysis after adjusting for age, BMI and prostate volume. When simultaneously adjusting for age, BMI, prostate volume and high-density lipoprotein cholesterol, serum insulin levels and SHBG levels were inversely correlated with serum PSA levels (P = 0.049 and P = 0.004, respectively), and testosterone levels were positively correlated with serum PSA levels (P = 0.039). In multivariate regression models, serum insulin levels and serum SHBG levels were significantly associated with serum PSA levels (both P < 0.001). Among the major pathogenic factors of metabolic syndrome, insulin resistance and sexual hormone changes may be the most significant contributors to the decline in serum PSA levels.


Process evaluation of a multicomponent intervention program (EXBELT) to reduce belt restraints in nursing homes.
The current study describes the process evaluation of a multicomponent intervention program (Expelling Belts [EXBELT]) to reduce the use of belt restraints in psychogeriatric nursing homes. The aim was to assess the feasibility and ascertain suggestions for optimization of the EXBELT program. A descriptive study comprising longitudinal elements. Fifteen psychogeriatric nursing home wards in 6 Dutch nursing homes. The study population consisted of 4 different groups of participants who took part in the intervention arm of the quasi-experimental study examining the effectiveness of EXBELT: nursing home staff who attended the final session of the educational program; 2 nurse specialists who delivered the educational program and did the consultations; 4 groups of delegates representing the nursing home associations where the EXBELT program was implemented; and the relatives of those residents in the intervention group who were restrained with a belt at the start of the study. Both quantitative and qualitative data were collected from the study population. Data were assessed by means of self-administered questionnaires, recording forms, group interviews, telephone interviews, and monthly meetings. The EXBELT study was largely performed according to protocol and very well received by nursing home staff as well as resident's relatives. Suggestions to improve the EXBELT program include the addition of examples of how to communicate about the policy change, improving the reach of the intended target population, adding more case-based learning strategies, and embedding the available consultants more proactively. The implementation of EXBELT was highly successful in the current research population and is likely to be feasible in psychogeriatric nursing homes in general.


Modified and simplified western blotting protocol: use of intermittent microwave irradiation (IMWI) and 5% skim milk to improve binding specificity.
A modified western blotting protocol was developed to increase the binding specificity of antigens and antibodies, using intermittent microwave irradiation (IMWI) with seven antibodies and two cell lines. The method was based on IMWI of the blotting membrane in the immunoblotting step using 5% skim milk as the diluting buffer. For some antibodies against p53, CDK4 and cyclinE, there were no distinct differences between the IMWI(+) and IMWI(-) counterparts; but improvement over the standard protocol was noted in both. For some antibodies, such as the polyclonal antibody against tubulin and the monoclonal antibodies against beta-tubulin, cyclinA and cyclinB1 (which were otherwise difficult to obtain good results with), IMWI was extremely effective, resulting in clear, specifically binding bands and a clean background. Moreover, the times were reduced from 8 to 3 h. Both the IMWI(+) and IMWI(-) protocols can be applied as simple, rapid and highly specific detection techniques for applications with various antigens, reducing background 'noise' to a minimum.


beta-Glucuronidase activation of latent aggression-promoting cues in mouse bladder urine.
The present study was designed to investigate the chemical properties of the aggression-promoting cues present in bladder urine of male mice. The results of the first experiment confirmed earlier work by demonstrating the presence of an aggression-promoting chemosignal in bladder urine. In Experiment 2, behavioral assays were separately performed on the organic and aqueous layers of bladder urine obtained by repeated dichloromethane extractions. Only the combined organic layers of the initial three extractions demonstrated behavioral activity. A fourth extraction showed no behavioral activity for both organic and aqueous layers. However, the findings of Experiment 3 showed that incubation of the aqueous layer from the third CH2Cl2 extraction in beta-glucuronidase can free additional aggression-promoting cues into a subsequent CH2Cl2 extraction. It is concluded that two forms of the aggression-promoting chemosignal are present in bladder urine. One is lipophilic and behaviorally active, whereas the other is conjugated, possessing latent chemosignal properties.


Off-resonance rotating-frame amide proton spin relaxation experiments measuring microsecond chemical exchange in proteins.
NMR spin relaxation in the rotating frame (R(1rho)) is a unique method for atomic-resolution characterization of conformational (chemical) exchange processes occurring on the microsecond time scale. Here, we use amide 1H off-resonance R(1rho) relaxation experiments to determine exchange parameters for processes that are significantly faster than those that can be probed using 15N or 13C relaxation. The new pulse sequence is validated using the E140Q mutant of the C-terminal domain of calmodulin, which exhibits significant conformational exchange contributions to the transverse relaxation rates. The 1H off-resonance R(1rho) data sample the entire relaxation dispersion profiles for the large majority of residues in this protein, which exchanges between conformations with a time constant of approximately 20 micros. This is in contrast to the case for 15N, where additional laboratory-frame relaxation data are required to determine the exchange parameters reliably. Experiments were performed on uniformly 15N-enriched samples that were either highly enriched in 2H or fully protonated. In the latter case, dipolar cross-relaxation with aliphatic protons were effectively decoupled to first order using a selective inversion pulse. Deuterated and protonated samples gave the same results, within experimental errors. The use of deuterated samples increases the sensitivity towards exchange contributions to the 1H transverse relaxation rates, since dipolar relaxation is greatly reduced. The exchange correlation times determined from the present 1H off-resonance R(1rho) experiments are in excellent agreement with those determined previously using a combination of 15N laboratory-frame and off-resonance R(1rho) relaxation data, with average values of [see text] and 21 +/- 3 micros , respectively.


Relationship of smoking to peripheral arterial disease.
Smoking is the most prevalent 'risk factor' causing atherosclerosis. The association is strongest for disease in arteries to the legs. Continued smoking worsens claudication, increases the risk of progression to gangrene, and decreases long-term patency rates of arterial reconstructions.


Optimization and validation of a QuEChERS-based method for the simultaneous environmental monitoring of 218 pesticide residues in clay loam soil.
A modified QuEChERS method was optimized, validated and verified for the extraction of 218 pesticide residues in agricultural soil samples. The 218 analytes are extracted using a single step, without clean-up, with matrix-matched calibration, and two complementary techniques: liquid and gas chromatography tandem triple quad mass spectrometry (LC-MS/MS and GC-MS/MS). Some of the parameters such as salts, acidity of the extraction solvent, sample moisture and some mechanical changes in the procedure were optimized to improve the overall performance for the target compounds and the soil matrix. The method was fully validated on a representative agricultural soil sample of the Canary Islands (clay loam soil) in terms of linearity, accuracy and precision. To avoid matrix effects, matrix-matched calibration curves (R2 ≥ 0.99) were used for all target analytes. 100% of the compounds can be quantified with limits of quantification (LOQ) lower than the limit typically used in soils (50 ng g-1), with 92% of compounds presenting a LOQ that is at least 10 times lower than that normally required. The limits of detection (LOD) ranged between 0.024 and 6.25 ng g-1. The validated method was applied to a series of actual samples of agricultural soil (n = 18). In addition, as a further verification of its potential, the results of the application of the method in the investigation of clay loam soil samples that were obtained from underneath wildlife carcasses in the context of an environmental forensic investigation are also presented.


Cytogenetic studies on the adult T-cell leukemia in Japan.
Cytogenetic studies were performed on 16 patients with ATL seen in Northern Kyushu island; nine were patients with acute type leukemia, one with crisis type and five with lymphoma type. The serum antibody for HTLV-1 (ATLA) was positive in all patients and the phenotype of ATL cells were ERFC+, OKT3+, OKT4+, OKT6-, OKT8-, OKT10+, OKla1+/- and Tac+. Abnormal findings of chromosomes were observed in 15 patients. Thirteen patients were in near diploid range. One patient was in triploid range and one patient was in tetraploid range. The polyploid karyotypes were found only in lymphoma type patients. Trisomy 3 and trisomy 7 were observed each in three patients with acute type of ATL. The most frequent abnormal rearrangement was observed in the long arm of chromosome 6 and the break occurred at band 6q15 and 6q21 each in four patients in this series.


Effect of phenol on the GABAAR-coupled Cl-/HCO3--ATPase from fish brain: An in vitro approach on the enzyme function.
Phenol (C6H5OH) has a toxic effect on the central nervous system of animals and humans. The Cl-/HCO3--ATPase from the plasma membranes of animal brains is the primary active P-type Cl--transporting system that is coupled to GABAA receptor (GABAAR). In this paper, we used an in vitro approach to assess the effects of phenol (1-500μM) on the functional parameters of the Cl-/HCO3--ATPase isolated from the fish brain. The enzyme is insensitive to phenol in the presence of Cl- or HCO3- in the incubation medium. By contrast, in the presence of Cl-/HCO3-, phenol inhibits (I50=27μM) both the enzyme activity and its participation in ATP-dependent Cl- transport through the membranes of artificial liposomes. Enriched plasma membranes and purified enzyme preparations were separated using hrCNE-PAGE. The ATPase activity in native gels was detected in the presence of phenol (100μM). Detection of ATPase activity in a purified preparation, showed a native protein of 300kDa, in agreement with western blot analysis with antibodies against GABAAR β3 subunits. SDS-PAGE showed that one subunit with a molecular weight of 56kDa was directly phosphorylated by γ-32P-ATP and dephosphorylated in the presence of phenol. The in vitro approach described in this work allowed the first demonstration that GABAAR-coupled Cl-/HCO3--ATPase can be a protein marker for assessment of the toxicity of phenolics on the central nervous system.


Persistent hypomagnesemia following cisplatin chemotherapy for testicular cancer.
Twenty-nine patients with nonseminomatous germ cell tumors of the testis have been followed for a median of 1.9 years (range 0.3-3.6) following completion of cisplatin-containing combination chemotherapy. Twenty-two of the 29 patients (76%) became hypomagnesemic during chemotherapy and, of these, 11 (50%) have remained persistently hypomagnesemic for as long as 3 years following discontinuation of cisplatin treatment. In the remaining patients, serum Mg levels returned to normal a median of 0.6 years (range, 0.2-2.1) after completion of chemotherapy. In eight of nine persistently hypomagnesemic patients studied, urinary Mg excretion was inappropriately elevated. Symptoms attributable to hypomagnesemia were rarely reported, although muscle cramps, twitching, or mild tremor were noted by the most severely hypomagnesemic patients. Continued followup of these patients is required to determine the effects of chronic hypomagnesemia in man.


Impact of planning organ at risk volume margins and matching method on late gastrointestinal toxicity in moderately hypofractionated IMRT for locally advanced pancreatic ductal adenocarcinoma.
This study examined the differences in late gastrointestinal (GI) toxicities in moderately hypofractionated intensity-modulated radiation therapy (IMRT) for locally advanced pancreatic ductal adenocarcinoma (LA-PDAC) by changing the planning organs at risk volume (PRV) margin and the target matching method and assessed the causes of adverse events. We examined 37 patients with LA-PDAC who underwent moderately hypofractionated IMRT between 2016 and 2020 at our institution; 23 patients were treated with wide PRV margins and soft tissue matching (Protocol A) and 14 with narrow PRV margins and fiducial marker matching (Protocol B). The GI toxicities, local control (LC) rate, and overall survival (OS) were assessed for each protocol. The initially planned and daily doses to the gross tumor volume (GTV), stomach, and duodenum, reproduced from cone-beam computed tomography, were evaluated. The late GI toxicity rate of grades 3-4 was higher in Protocol B (42.9%) than in Protocol A (4.3%). Although the 2-year LC rates were significantly higher in Protocol B (90.0%) than in Protocol A (33.3%), no significant difference was observed in OS rates. In the initial plan, no deviations were found for the stomach and duodenum from the dose constraints in either protocol. In contrast, daily dose evaluation for the stomach to duodenal bulb revealed that the frequency of deviation of V3 Gy per session was 44.8% in Protocol B, which was significantly higher than the 24.3% in Protocol A. Reducing PRV margins with fiducial marker matching increased GI toxicities in exchange for improved LC. Daily dose analysis indicated the trade-off between the GTV dose coverage and the irradiated doses to the GI. This study showed that even with strict matching methods, the PRV margin could not be reduced safely because of GI inter-fractional error, which is expected to be resolved with online adaptive radiotherapy.


Pitfalls of FNA diagnosis of thymic tumors.
Fine-needle aspiration (FNA), a minimally invasive and cost-effective procedure, often is used in the initial diagnosis of thymic lesions. However, the diagnosis can be challenging. Knowledge of the diagnostic pitfalls is important to improve diagnostic accuracy. The authors retrospectively searched the pathology database of The University of Texas MD Anderson Cancer Center for FNA cases using the keywords "thymoma" or "thymic" in cytologic diagnoses or in corresponding final histologic diagnoses rendered from January 2002 to June 2018. The authors reviewed the FNA diagnostic accuracy and pitfalls in comparison with the final histologic diagnoses. A total of 118 FNA cases were identified from 115 patients. The FNA diagnoses were concordant with the final pathologic diagnoses in 110 cases (93.2%), including thymoma (97 cases), atypical thymoma (5 cases), and thymic carcinoma (8 cases). Discrepant FNA and final diagnoses were noted in 8 tumors (6.8%): thymoma versus atypical thymoma/thymic carcinoma (3 tumors), thymoma versus lymphoma (2 tumors), suspicious for lymphoma versus thymoma (1 tumor), and T-lymphoblastic lymphoma versus thymoma (2 tumors). Factors contributing to misinterpretation included intrinsic limitations of the FNA sample (sampling error and a lack of histologic architecture information) and similarities of the cytologic and immunophenotypic features of lymphocyte-rich thymoma and T-lymphoblastic lymphoma. An accurate FNA diagnosis of thymic tumors can be rendered in the majority of cases. Diagnostic pitfalls can be encountered in rare cases. It is important to handle each case carefully to avoid erroneous diagnoses that may lead to inappropriate treatment.


Is it possible to have impaired neurocognition but good social cognition in schizophrenia?
Social cognitive impairment in schizophrenia is common and associated with poor functional outcome. While correlations in the moderate range suggest that social cognition and neurocognition are separate but overlapping domains, less is known about whether intact neurocognition represents a "necessary but not sufficient" condition for intact social cognition, as has been suggested. In the present study we examined the following in a sample of 119 psychiatrically stable outpatients with schizophrenia: 1) correlations between multiple social cognitive measures and neurocognition, 2) the predictive value of neurocognitive domains in explaining social cognitive performance, and 3) the co-occurrence of social cognitive and neurocognitive impairment within participants. While ¼ of participants showed intact overall neurocognition and impaired overall social cognition, only one participant had normal-range social cognition and impaired neurocognition. Results support the notion that normal range neurocognition is a necessary though not necessarily sufficient building block for good social cognitive performance.


Social stress-induced hypothyroidism is attenuated by antidepressant treatment in rats.
Although serotonergic system has been classically implicated in mood modulation, there has been relatively little study on the relationship between this system and thyroid hormones (TH) economy in stress models. When TH are studied, the effects of stress on thyroid function seems to be complex and depend on the kind and time of stress which counts for the elusiveness of mechanisms underlying changes in TH economy. Herein, we hypothesized that serum TH are affected in a time-dependent fashion after repeated social stressful stimuli and serotonergic system is implicated in these changes. Therefore, we aimed to investigate the possible alterations in thyroid hormone economy and type 1 (D1) and type 2 (D2) deiodinase activity in a model of social defeat stress. Thereafter, we tested the responsiveness of these changes to fluoxetine treatment. Both short (STS) and a long-term (LTS) stress were performed. Blood samples were drawn just before and 1 (STS) or 4 and 8 weeks (LTS) after the beginning of stress to assess serum T4, T3 and corticosterone. Deiodinases activity was assessed at the end of each protocol. Stress-induced behavior studied in open field arena and hypercorticosteronemia were mainly observed in LTS (week 4). Stress-induced behavior was associated to hypothyroidism which occurred before, since week 1 in stressed group. Serum TH was restored to control levels in week 8, when behavior changes were not observed anymore, and was mainly associated with high brown adipose tissue D2 activity since thyroid and liver D1 activity were low or normal in the STS and LTS respectively in stressed rats compared to control. Antidepressant study revealed that fluoxetine treatment (10mg/kg po during four weeks) fully reversed stress-induced behavior and normalized serum T4, but not T3 levels and hypercorticosteronemia in stressed group compared to control. The current work adds new concepts concerning TH metabolism changes induced by social stress and suggests that serotonergic system impairment may take part in the key events which ultimately lead to hypothyroxinemia and behavioral changes induced by chronic social defeat. This article is part of a Special Issue entitled 'Anxiety and Depression'.


BDNF rs6265 Met carriers with alcohol use disorder show greater age-related decline of N-acetylaspartate in left dorsolateral prefrontal cortex.
Brain-derived neurotrophic factor (BDNF) is implicated in neuronal and glial cell growth and differentiation, synaptic plasticity, and apoptotic mechanisms. A single-nucleotide polymorphism of the BDNF rs6265 gene may contribute to the pattern and magnitude of brain metabolite abnormalities apparent in those with an Alcohol Use Disorder (AUD). We predicted that methionine (Met) carriers would demonstrate lower magnetic resonance spectroscopy (MRS) measures of N-acetylaspartate level (NAA) and greater age-related decline in NAA than valine (Val) homozygotes. Veterans with AUD (n=95; 46±12 years of age, min = 25, max = 71) were recruited from VA Palo Alto residential treatment centers. Single voxel MRS, at 3 Tesla, was used to obtain NAA, choline (Cho) and creatine (Cr) containing compounds from the left dorsolateral prefrontal cortex (DLPFC). Metabolite spectra were fit with LC Model and NAA and Cho were standardized to total Cr level and NAA was also standardized to Cho. Val/Met (n=35) showed markedly greater age-related decline in left DLPFC NAA/Cr level than Val/Val (n=60); no differences in mean metabolite levels were observed between Val/Met and Val/Val. Val/Met demonstrated greater frequency of history of MDD and higher frequency of cannabis use disorder over 12 months prior to study. The greater age-related decline in left DLPFC NAA/Cr and the higher frequency of MDD history and Cannabis Use disorder in BDNF rs6265 Met carriers with AUD are novel and may have implications for non-invasive brain stimulation targeting the left DLFPC and other psychosocial interventions typically utilized in the treatment of AUD.


Left mixed laryngocele in absence of risk factors: A case report and review of literature.
Laryngocele is an uncommon benign cystic dilatation of the laryngeal saccule that communicates with the laryngeal lumen and contains air. On the basis of its localization, it can be traditionally classified in internal, external, or mixed. Usually unilateral and rarely bilateral, it may be congenital or acquired. It most often appears later in life without important symptoms except for cervical swelling. Here, together with a review of literature, we report the case of a 72-year-old man, smoker but without other specific risk factors, who presented laryngeal dyspnea for about one year. Neck CT scan performed during a previous hospitalization for respiratory failure revealed a left mixed laryngocele that was later surgically removed with cervicotomic access. The patient was discharged after one week. One month after surgery, we confirmed the absence of disease with video laryngoscopy.


Growing relevance of reports of adolescent cyberbullying victimization among adult outpatients.
In the general population, prevalence rates of cyberbullying victimization have continuously increased over the past decades. However, the extent to which these increasing numbers affect clinical populations seeking treatment in outpatient services remains an open question. The present study sought to examine whether the increase of cyberbullying victimization is also reflected by increased reports of cyberbullying victimization in a clinical outpatient population. In addition, we assessed the incremental contribution of experiences of cyberbullying in the prediction of psychological symptoms when controlling for histories of childhood maltreatment and offline peer victimization. For this purpose, we analyzed routine data from N = 827 outpatients who had sought treatment at a University outpatient clinic for psychotherapy between 2012 and 2021 in a cross-sectional study design. Analyses showed that 8.3% of the patients born in the years 1980 to 2002 indicated the experience of cyberbullying victimization in their adolescence. The rate of reported cyberbullying victimization increased from 1 to 3% in patients born in the years 1980 to 1987 to 24% in patients born in the year 2000. A logistic regression revealed that patients born in the years 1995-2002 were up to nineteen times as likely to report cyberbullying victimization as patients born in the years 1980-1982. In addition, hierarchical multiple regression analyses indicated that cyberbullying victimization significantly accounted for an incremental proportion of variance (1%) in the prediction of psychological symptom distress after controlling for child maltreatment and offline peer victimization. In conclusion, this retrospective survey indicates an increase of the clinical relevance of cyberbullying victimization both in frequency of and potential contribution to etiology. Raising attention to cyberbullying in clinical care and research seems to be justified and warranted.


Effects of different strains fermentation on the sensory and nutritional properties of soy-based yogurt.
Soy protein is the only full plant protein that is comparable to animal protein. Soy whey contains a variety of nutrients including isoflavones and oligosaccharides. Additionally, different strains have profound influence on functional metabolism. Most prospective studies used mixed strain fermented yogurt, but few studies on single strain fermented yogurt. The present study aimed to ferment nutritious and healthy soy-based yogurt using a single strain and to provide technical support for the reuse of soy whey. Streptococcus salivarius subsp. thermophilus HCS07-002, Bifidobacterium animalis subsp. lactis HCS04-001 and Lactiplantibacillus plantarum HCS03-084 had strong growth and metabolic activities. Bifidobacterium animalis subsp. lactis HCS04-001 fermentation raised the texture and rheological properties of yogurt and enriched the flavor substances in the yogurt, resulting in a good quality soy-based yogurt. The contents of arginine, glutamic and proline were greatly affected by the fermentation of different strains. The fermentation of B. animalis subsp. lactis HCS04-001 was beneficial to the enrichment of soy isoflavone and equol in yogurt, and enhanced antioxidant activity of yogurt. Our findings indicated that yogurt fermented with B. animalis subsp. lactis HCS04-001 had the best sensory and nutritional properties, which provides valuable insights into the selection of suitable strains to improve the quality and nutritional value of plant yogurt. © 2023 Society of Chemical Industry.


Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations.
Most missense long QT syndrome type 2 (LQTS2) mutations result in Kv11.1 channels that show reduced levels of membrane expression. Pharmacological chaperones that rescue mutant channel expression could have therapeutic potential to reduce the risk of LQTS2-associated arrhythmias and sudden cardiac death, but only if the mutant Kv11.1 channels function normally (i.e. like WT channels) after membrane expression is restored. Fewer than half of mutant channels exhibit relatively normal function after rescue by low temperature. The remaining rescued missense mutant Kv11.1 channels have perturbed gating and/or ion selectivity characteristics. Co-expression of WT subunits with gating defective missense mutations ameliorates but does not eliminate the functional abnormalities observed for most mutant channels. For patients with mutations that affect gating in addition to expression, it may be necessary to use a combination therapy to restore both normal function and normal expression of the channel protein. In the heart, Kv11.1 channels pass the rapid delayed rectifier current (IKr ) which plays critical roles in repolarization of the cardiac action potential and in the suppression of arrhythmias caused by premature stimuli. Over 500 inherited mutations in Kv11.1 are known to cause long QT syndrome type 2 (LQTS2), a cardiac electrical disorder associated with an increased risk of life threatening arrhythmias. Most missense mutations in Kv11.1 reduce the amount of channel protein expressed at the membrane and, as a consequence, there has been considerable interest in developing pharmacological agents to rescue the expression of these channels. However, pharmacological chaperones will only have clinical utility if the mutant Kv11.1 channels function normally after membrane expression is restored. The aim of this study was to characterize the gating phenotype for a subset of LQTS2 mutations to assess what proportion of mutations may be suitable for rescue. As an initial screen we used reduced temperature to rescue expression defects of mutant channels expressed in Xenopus laevis oocytes. Over half (∼56%) of Kv11.1 mutants exhibited functional gating defects that either dramatically reduced the amount of current contributing to cardiac action potential repolarization and/or reduced the amount of protective current elicited in response to premature depolarizations. Our data demonstrate that if pharmacological rescue of protein expression defects is going to have clinical utility in the treatment of LQTS2 then it will be important to assess the gating phenotype of LQTS2 mutations before attempting rescue.


Effects of interdisciplinary teamwork on patient-reported experience of cancer care.
Interdisciplinary teamwork (ITW) is deemed necessary for quality cancer care practices. Nevertheless, variation in ITW intensity among cancer teams is understudied, and quantitative evidence of the effect of different ITW intensities among cancer teams on patients' perceived experience of care is limited. This study aims to compare patient-reported experience measures (PREMs) of cancer outpatients followed by teams characterized by high vs. low ITW intensity. The study is designed as an ex post facto quasi-experimental study. Participants (n = 1379) were recruited in nine outpatient oncology clinics characterized by different ITW intensities. ITW intensities were evaluated using the characteristics of structure (team composition and size) and process (interactions among team members), as per West's seminal work on team effectiveness. ITW intensity was dichotomized (high vs. low ITW intensity). PREMs were classified and measured using validated scales corresponding to six dimensions: Prompt access to care, Person-centred response, Quality of patient-professional communication, Quality of the care environment, Continuity of care, and Results of care. Dichotomous variables were created for each dimension (positive vs. less positive experience). Multiple logistic regression analyses were performed to assess the association between ITW intensities and the six PREMs dimensions, while controlling for patient and organizational characteristics. PROC GENMOD was used to fit logistic models for categorical variables. Outpatients treated by teams characterized by high ITW intensity reported almost four times more positive perceptions of Prompt access to care compared to patients treated by low ITW intensity teams (OR = 3.99; CI = 1.89-8.41). High ITW intensity also positively affected patients' perceptions of Quality of patient-professional communication (OR = 2.37; CI = 1.25-4.51), Person-centred response (OR = 2.11; CI = 1.05-4.24], and Continuity of care (OR = 2.18; CI = 1.07-4.45). No significant association was found between ITW intensity and perceived Results of care (OR = 1.31; CI = 0.68-2.52) or Quality of the care environment (OR = 0.66; CI = 0.31-1.39). This study provides empirical evidence, from the patient's perspective, that ITW intensity affects some critical aspects of patient-reported quality of care. Future research will allow explaining how and why ITW structure and processes may contribute to positive cancer care experiences.


Structural Distortion-Induced Charge Gradient Distribution of Co Ions in Delithiated LiCoO2 Cathode.
Layered LiCoO2 has drawn tremendous attention as a modeling cathode for Li-ion batteries, while its structural instability, especially in the high delithiation region, remains unsolved. With the aim of revealing the structural fundamentals, LiCoO2 electrodes are investigated at a long delithiation range using both in situ and ex situ techniques. In the highly delithiated LiCoO2 electrode, the unique charge compensation process leads to a spatial charge gradient of Co2+/Co3+/Co4+ ions from surface to bulk, which can be further manipulated by structural distortion, Li extraction, and surface side reactions. The coordinated surface oxygen is shown to be electrochemically active and fully reversible in participating in the charge compensation during cycling. Moreover, the active lattice O can be significantly stabilized by introducing the undesired surface Li-Co antisites, which also play an effective role in accommodating the internal stress induced by volume changes. These findings effectively bridge the structural changes with the Li+/e- migration kinetics to elucidate the degradation of LiCoO2 cathode upon delithiation, demonstrating a rewarding avenue for improving the electrochemical performance of LiCoO2 itself and developing high energy density cathodes for the battery community as well.


Metabolic indices shift in the hypothalamic-neurohypophysial system during lactation: implications for interpreting their relationship with neuronal activity.
Metabolic indices of neuronal activity are thought to predict changes in the frequency of action potentials. There are stimuli that do not shift action potential frequency but change the temporal organization of neuronal firing following modifications of excitatory inputs by inhibitory synaptic activation. To our knowledge it is unknown whether this kind of stimulus associates with adjustments of metabolic markers of neuronal activity. Here, we used the hypothalamic-neurohypophysial system of lactating rats to address whether shifts in the temporal organization of neuronal firing relate with modifications of metabolic markers of neuronal activity. Cytochrome oxidase activity, (3)H-2-deoxyglucose uptake, and the area occupied by blood vessels increased in the paraventricular nucleus and neurohypophysis of lactating rats, as compared with their virgin counterparts. Taken together, these results suggest that metabolic demands denote shifts in the temporal organization of action potentials related with the adjustment of excitatory synaptic activation, and support that changes in metabolic markers do not necessarily reflect shifts in the frequency of action potentials.


Determination of hopanoid levels in bacteria using high-performance liquid chromatography.
A reverse-phase HPLC method to detect and quantify levels of hopanoids in bacteria has been developed. Chromophores have been introduced by derivatization and the levels of the C35 hopanoids and their conjugates can be measured in bacterial lipid extracts down to picomole levels. Some structural variations of the complex lipids were detected after derivatization and were easily purified using the same HPLC system. Zymomonas mobilis and Rhodospirillum rubrum extracts were examined using this system and different structural examples of the lipids were detected. The relative levels of the different triterpenes were very dependent on the growth conditions.


Macrocyclic Dinuclear Palladium Complex as a Novel Doubly Threaded [3]Rotaxane Scaffold and Its Application as a Rotaxane Cross-Linker.
A dinuclear PdII complex possessing a cyclic ligand was developed as a novel doubly threaded [3]rotaxane scaffold and applied as a rotaxane cross-linker reagent. The dinuclear complex (PdMC)2 was prepared by one-step macrocyclization followed by the double palladation reaction. 1 H NMR analysis and UV/Vis measurements revealed the formation of a doubly threaded pseudo[3]rotaxane by the complexation of (PdMC)2 with 2 equivalents of 2,6-disubstituted pyridine 3 through double metal coordination. The treatment of (PdMC)2 with 2 equivalents of 4-vinylpyridine (VP) afforded a doubly threaded [3]rotaxane cross-linker (PdMC-VP)2 . Radical co-polymerization of VP and t-butylstyrene in the presence of (PdMC-VP)2 afforded a stable rotaxane cross-linked polymer (RCP). An elastic RCP was also prepared by using n-butyl acrylate as a monomer. The obtained RCPs exhibited higher swelling ability and higher mechanical toughness compared with the corresponding covalent cross-linked polymers.


Self-care model based on the theory of unpleasant symptoms in patients with heart failure.
This study aimed to test and develop the self-care model based on the theory of unpleasant symptoms in patients with HF. Although self-care may reduce unpleasant symptoms of heart failure (HF), reported rates of effective self-care in HF patients are very low. Modifiable factors, including disease severity, anxiety, depression, social support, unpleasant symptoms, and self-efficacy are considered to influence self-care, but little is known about their overall impact on self-care. A model-testing design was used. Covariance structure analysis using the maximum likelihood method was used to evaluate the hypothetical model. A total of 209 subjects participated in the study. The model-fit indexes of the final model were χ2 = 163.473, Normed χ2 = 1.796, RMSEA = 0.054, IFI = 0.986, CFI = 0.986, GFI = 0.915, and AGFI = 0.873. Disease severity and anxiety had an indirect effect on self-care through unpleasant symptoms. Depression and social support had an indirect effect on self-care through self-efficacy. Lower unpleasant symptoms and higher self-efficacy were associated with greater self-care. These predictors explained 61.9% of variance in self-care. Findings from this study could underscore the need to consider nursing strategies that relieve unpleasant symptoms and improve self-efficacy to enhance self-care in HF patients.


The design of light-handed regulation of airports: Lessons from experience in Australia and New Zealand.
The difficulties experienced with traditional forms of economic regulation of airports involving direct control of prices have led to an interest in light-handed regulatory frameworks. Experience with light-handed regulation of airports is primarily confined to Australia and New Zealand. The paper examines the design features of light-handed regulation in Australia and New Zealand in relation to the stated objectives associated with the introduction of light-handed regulation. The paper identifies important aspects associated with the design of light-handed regulation including the incorporation of a credible threat of stronger regulation and the characteristics of this, and an apparent trade-off in objectives achieved with different approaches to light-handed regulation.


Risk of incident diabetes post-COVID-19: A systematic review and meta-analysis.
It remains undetermined whether burden of diabetes newly detected during acute COVID-19 persist in post-acute COVID phase. This meta-analysis was conducted to summarize the available literature and provide a pooled estimate of the risk of developing incident diabetes following hospital discharge or at least 28 days after the COVID-19 diagnosis compared to matched controls or severity matched influenza/ non-COVID-19 acute upper respiratory tract infections (AURI). Pooled analysis of 5787,027 subjects from four observational studies showed 59 % higher risk of developing incident diabetes in post-acute COVID-19 phase versus healthy controls (HR:1.59; 95 % CI:1.40-1.81, p < 0.001, I2=94 %, random-effects model). The high degree of heterogeneity in pooled estimate can be attributed to difference in demographic characteristics, hospitalization rates or disease severity between study subjects. Pooling data from three studies, higher risk of incident diabetes was also observed following COVID-19 versus severity matched non-COVID-19 respiratory tract infections (moderate-severe/hospitalized cases, HR 1.52; 95 % CI: 1.36-1.70, p < 0.01, I2=0 %, fixed-effects model; mild cases, HR 1.22; 95 % CI: 1.14-1.31, p < 0.001; I2=0 %, fixed-effects model). Majority of studies had median follow-up period of around 4 months. In view of several limitations due to retrospective design of these studies, prospective studies with long term follow-up are warranted.


Is Cognitive Reserve a Determinant of Functional and Mental Health in Older People of the Sardinian Blue Zone? A Mediational Approach.
The main purpose of this study was to examine the mediating role of cognitive reserve in the relationship between functional health (expressed through the amount and intensity of performed physical activity objectively assessed using wearable accelerometers) and psychological well-being (i.e., assessed in terms of self-reported depressive signs) of older people living in an area of exceptional longevity, the so-called Sardinian Blue Zone. A further goal was to investigate the impact of gender on the cognitive reserve and physical health of our participants, using global cognitive functioning as a covariate. A battery of tests assessing motor efficiency, cognitive reserve, global cognitive functioning, and self-reported depressive symptoms was individually presented to 120 community dwellers (Mage = 82 years, SD = 8.4 years) of the Sardinian Blue Zone. Significant associations were found between cognitive reserve, motor efficiency, and self-reported depressive signs. Moreover, three mediation analyses documented that distinct indexes of cognitive reserve and motor efficiency explain 27.2-31% of the variance in the self-reported depression condition. Following this, it was also found that people with scarce cognitive reserve tended to exhibit significant signs of depression and showed worse motor abilities. In addition, after controlling for the effect of global cognitive functioning, motor efficiency, and cognitive reserve were generally more preserved in males than in females. Overall, these findings suggest that cognitive reserve is a compensatory resource that contributes significantly to the enhancement of health-related quality of life in the last decades of life.


A systematic review on sleep alterations anticipating the onset of bipolar disorder.
Sleep alterations are frequent occurrence in Bipolar Disorder (BD), both in acute and interepisodic phases. Sleep alterations have been also described both long before BD onset, as aspecific risk syndromes, or as immediate prodromes of BD onset. The aim of the present study is to systematically review the relationship between sleep alterations anticipating for the full-blown onset of BD, both in general and according to specific polarities of onset. A systematic literature research according to PRISMA statement and considering: 1. prospective studies about BD patients' offspring with sleep alterations who later developed BD. 2. prospective studies assessing patients with sleep disorders who later developed BD. 3. retrospective studies on BD patients where sleep alterations before BD onset of the disease were reported. A total of 16 studies were included in this review. Sleep disturbances may frequently appear 1 year before the onset of BD or more, often during childhood or adolescence. A decreased need for sleep may precede the onset of the illness, specially a manic episode, while insomnia appears to anticipate either a manic or a depressive episode. Hypersomnia seems to precede bipolar depressive episodes. Sleep alterations frequently appear long before the onset of BD, and appear to be related specifically to the polarity of the index episode. The detection and treatment of sleep alterations in special high risk populations may help achieving an earlier detection of the illness.


Alkaline mineral water lowers bone resorption even in calcium sufficiency: alkaline mineral water and bone metabolism.
Dietary acid charge enhances bone loss. Bicarbonate or alkali diet decreases bone resorption in humans. We compared the effect of an alkaline mineral water, rich in bicarbonate, with that of an acid one, rich in calcium only, on bone markers, in young women with a normal calcium intake. This study compared water A (per litre: 520 mg Ca, 291 mg HCO(3)(-), 1160 mg SO(4)(-), Potential Renal Acid load (PRAL) +9.2 mEq) with water B (per litre: 547 mg Ca, 2172 mg HCO(3)(-), 9 mg SO(4)(-), PRAL -11.2 mEq). 30 female dieticians aged 26.3 yrs (SD 7.3) were randomized into two groups, followed an identical weighed, balanced diet (965 mg Ca) and drank 1.5 l/d of the assigned water. Changes in blood and urine electrolytes, C-telopeptides (CTX), urinary pH and bicarbonate, and serum PTH were measured after 2 and 4 weeks. The two groups were not different at baseline, and showed a similar increase in urinary calcium excretion. Urinary pH and bicarbonate excretion increased with water B, but not with water A. PTH (p=0.022) and S-CTX (p=0.023) decreased with water B but not with water A. In calcium sufficiency, the acid calcium-rich water had no effect on bone resorption, while the alkaline water rich in bicarbonate led to a significant decrease of PTH and of S-CTX.


Bacteroides fragilis endocarditis: a case report and review of literature.
Endocarditis due to Bacteroides fragilis is a rare disorder. This article describes a case of Bacteroides fragilis endocarditis associated with portal and superior mesenteric venous thrombosis in a patient without preexisting valvular heart disease and review the cases of endocarditis due to this anaerobic bacterium in medical literature since 1980.


Truncated amelogenin and LRAP transgenes improve Amelx null mouse enamel.
Amelogenin is the most abundant enamel protein involved in enamel mineralization. Our goal was to determine whether all three regions of amelogenin (N-terminus, C-terminus, central core) are required for enamel formation. Amelogenin RNA is alternatively spliced, resulting in at least 16 different amelogenin isoforms in mice, with M180 and LRAP expressed most abundantly. Soon after secretion by ameloblasts, M180 is cleaved by MMP20 resulting in C-terminal truncated (CTRNC) amelogenin. We aimed to determine whether the 2 transgenes (Tg), LRAP and CTRNC together, can improve LRAPTg/Amelx-/- and CTRNCTg/Amelx-/- enamel thickness and prism organization, which were not rescued in Amelx-/- enamel. We generated CTRNCTg/LRAPTg/Amelx-/- mice and analyzed developing and mature incisor and molar enamel histologically, by microCT, SEM and microhardness testing. CTRNCTg and LRAPTg overexpression together significantly improved the enamel phenotype of LRAPTg/Amelx-/- and CTRNCTg/Amelx-/- mouse enamel, however enamel microhardness was recovered only when M180Tg was expressed, alone or with LRAPTg. We determined that both LRAP and CTRNC, which together express all three regions of the amelogenin protein (N-terminus, C-terminus and hydrophobic core) contribute to the final enamel thickness and prism organization in mice.


Ribosomal mutations in Arcanobacterium pyogenes confer a unique spectrum of macrolide resistance.
Four macrolide-resistant Arcanobacterium pyogenes isolates contained A2058T, A2058G, or C2611G (Escherichia coli numbering) mutations in their 23S rRNA genes. While these mutations conferred resistance to erythromycin, oleandomycin, and spiramycin, they did not confer resistance to tylosin.


Comparing directly measured versus mathematically calculated free serum 25-hydroxy vitamin D level in children.
25-Hydroxy vitamin D (25(OH)D) is essential for calcium homeostasis and bone metabolism. The majority of serum 25(OH)D is bound to vitamin D-binding protein (VDBP) (~ 85%) and to albumin (~ 15%), with only a miniscule amount circulating as free 25(OH)D. Free 25(OH)D can be calculated mathematically by Bikle method from the concentrations of total 25(OH)D, VDBP, and albumin or measured directly by ELISA. A direct head-to-head comparison between the two methods has not been done in children. The objective of the study was to compare the mathematically calculated versus directly measured free 25(OH) vitamin D in children. Serum samples from 74 children (ages 1-19 years) were simultaneously analyzed for total 25(OH)D, serum albumin, VDBP, and free 25(OH)D. Pearson correlation analysis and Bland-Altman plot were used to evaluate agreement between the two methods. The mean age was 9.1 ± 5.1 years, with 61% boys, 76% Caucasians, and 24% African-Americans. The mean ± SD for total 25(OH)D was 38.7 ± 12.8 ng/mL, bioavailable 25(OH)D 3.1 ± 1.1 ng/mL, mathematically calculated free 25(OH)D 8.4 ± 3.2 pg/mL, and directly measured free 25(OH)D 8.9 ± 3.6 pg/mL. Pearson correlation reflected a significant correlation between mathematically calculated and directly measured free 25(OH)D (r = 0.66, p < 0.0005). Bland-Altman plot reflected a tight agreement within a 95% limit of agreement (mean = - 0.026 ± 2SD). The directly measured and mathematically calculated free 25(OH)D are in close agreement and are interchangeable. Depending on the local availability of instruments and methods, free 25(OH)D can be either directly measured or mathematically calculated.


Photodynamic therapy with WST09 (Tookad): quantitative studies in normal colon and transplanted tumours.
Photodynamic therapy (PDT) is attracting increasing interest for the safe destruction of localised tumours in a range of organs. However, most photosensitising drugs require a delay of hours to days between drug administration and light activation with skin photosensitivity that may last for weeks. WST09 (Tookad) is a new faster acting photosensitiser that clears within a few hours. In normal rat colon, after sensitisation with an intravenous bolus of WST09, light was delivered to a single point on the mucosa and the extent of PDT necrosis measured 3 days later. The lesion diameter was greatest with the highest dose of drug and light and the shortest drug light interval (DLI), falling rapidly with a DLI more than 5 min. In tumours transplanted subcutaneously or into the colon, the extent of necrosis only started falling with a DLI greater than 15 min, suggesting a possible window for tumour selectivity. Histological changes 3 days after PDT were essentially the same as those seen with longer acting photosensitisers. The lesion dimensions were comparable to the largest ones seen with other photosensitisers under similar experimental conditions. We conclude that WST09 is a powerful photosensitiser that produces PDT effects similar to those seen with longer acting drugs, but with the major advantages of a short DLI and rapid clearance.


The relationship between antidepressant response and tricyclic antidepressant plasma concentrations. A retrospective analysis of the literature using logistic regression analysis.
The relationship between the antidepressant effect of the tricyclic antidepressants and their plasma concentrations was reviewed. Logistic regression was utilised as an analytical tool to facilitate the evaluation. The currently available literature allowed the construction of 4 tricyclic data sets of sufficient size to warrant statistical analysis. Inspection of the distribution of the data and the logistic regression analyses resulted in several conclusions regarding the existence of 'therapeutic windows' for these drugs. Firstly, no relationship between amitriptyline plasma concentrations and therapeutic response was apparent. Secondly, curvilinear relationships were apparent for 2 of the other tricyclic antidepressants studied. The currently recommended therapeutic range of 60 to 150 micrograms/L for nortriptyline was found to be the range most likely to produce a positive antidepressant effect. Desipramine concentrations between 108 and 158 micrograms/L were most commonly associated with beneficial therapeutic responses. Finally, a linear relationship was noted for imipramine in which an imipramine therapeutic plasma concentration threshold of 244 micrograms/L and above was most commonly associated with a beneficial response to the drug.


An internet database for the classification and dissemination of information about hazardous chemicals and occupational diseases.
The amount of information about hazardous agents in the workplace exceeds the capacity of human memory. There is a need to accurately represent or map this scientific knowledge for digital storage and retrieval. A relational database of hazardous chemicals and occupational diseases was constructed by first collecting and sifting through the large volume of information. The information was indexed with a controlled vocabulary and documented with references to the scientific literature. The evolving database is available on the website of the National Library of Medicine. It enables users to browse categories and query by pick lists. Users can drill down to find specific information that may be useful for intervention and prevention. The large amount of information needed to support decisions concerning occupational exposures and diseases can be distilled, classified, and summarized in a relational database and disseminated by means of the World Wide Web to assist in the prevention of work-related diseases.


Characterization of indo-1 and quin-2 as spectroscopic probes for Zn2(+)-protein interactions.
1-[2-Amino-5-(6-carboxyindol-2-yl)phenoxyl]-2-(2'- amino-5'-methylphenoxy)ethane-N,N,N',N'-tetraacetic acid (indo-1) and 2-[2-(bis(carboxymethyl)amino-5-methylphenoxy) methyl]-6- methyl-8-[bis-(carboxymethyl)amino]quinoline (quin-2) are sensitive, spectral indicators for Zn2+. Additions of subsaturating Zn2+ to 10-80 microM indo-1 or quin-2 at pH 7.0 produce uv difference spectra with isosbestic wavelengths at 342 and 282 nm or at 342, 317, and 252 nm, respectively. Formation of 1:1 Zn2+:indicator complexes at pH 7.0 and 20 degrees C in the absence (presence) of 100 mM KCl gives delta epsilon max = -2.4 +/- 0.2 X 10(4) M-1 cm-1 at 367 nm (-2.1 +/- 0.2 X 10(4) M-1 cm-1 at 365 nm) for indo-1 and delta epsilon max = -2.7 +/- 0.1 X 10(4) M-1 cm-1 at 266 nm (-2.6 +/- 0.1 X 10(4) M-1 cm-1 at 265 nm) for quin-2. Competition experiments at pH 7.0 and 20 degrees C with indo-1 and quin-2 and also 4-(2-pyridylazo)resorcinol (PAR) as the second chelator in the absence (presence) of 100 mM KCl yield apparent affinity constants: K'A = 2.5 +/- 1.0 X 10(10) M-1 (6.2 +/- 0.5 X 10(9) M-1) for indo-1 binding Zn2+ and K'A = 9.4 +/- 3.3 X 10(11) M-1 (2.7 +/- 0.1 X 10(11) M-1) for quin-2 binding Zn2+. The above constants provide the basis for rapid steady-state spectrophotometric determinations of the affinity of a protein for Zn2+ with K'A approximately 10(10) - 10(13) M-1.(ABSTRACT TRUNCATED AT 250 WORDS)


Chemically Defined Production of Tri-Lineage Human iPSC-Derived Cardiac Spheroids.
Cardiac spheroids derived from human induced pluripotent stem cells (hiPSC-cardiac spheroids) represent a powerful three-dimensional (3D) model for examining cardiac physiology and for drug toxicity screening. Recent advances with self-organizing, multicellular cardiac organoids highlight the capability of directed stem cell differentiation approaches to recapitulate the composition of the human heart in vitro. Using hiPSC-derived cardiomyocytes (hiPSC-CMs), hiPSC-derived endothelial cells (hiPSC-ECs), and hiPSC-derived cardiac fibroblasts (hiPSC-CFs) is advantageous for enabling tri-cellular crosstalk within a multilineage system and for generating patient-specific models. Chemically defined medium containing factors needed to simultaneously maintain hiPSC-CMs, hiPSC-ECs, and hiPSC-CFs is used to produce the spheroid system. In this article, we present protocols to illustrate the methods for conducting small-molecule-mediated differentiations of hiPSCs into cardiomyocytes, endothelial cells, and cardiac fibroblasts, as well as to assemble the fully integrated cardiac spheroids. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Maintenance and expansion of hiPSCs Basic Protocol 2: Differentiation of hiPSCs into cardiomyocytes Basic Protocol 3: Differentiation of hiPSCs into vascular endothelial cells Basic Protocol 4: Differentiation of hiPSCs into cardiac fibroblasts Basic Protocol 5: Production of hiPSC-derived cardiac spheroids.


A Unified Framework for Reservoir Computing and Extreme Learning Machines based on a Single Time-delayed Neuron.
In this paper we present a unified framework for extreme learning machines and reservoir computing (echo state networks), which can be physically implemented using a single nonlinear neuron subject to delayed feedback. The reservoir is built within the delay-line, employing a number of "virtual" neurons. These virtual neurons receive random projections from the input layer containing the information to be processed. One key advantage of this approach is that it can be implemented efficiently in hardware. We show that the reservoir computing implementation, in this case optoelectronic, is also capable to realize extreme learning machines, demonstrating the unified framework for both schemes in software as well as in hardware.


Phase Ia dose-escalation trial with the BET protein inhibitor BI 894999 in patients with advanced or metastatic solid tumours.
Bromodomain and extraterminal domain (BET) inhibitors have demonstrated efficacy in solid tumours and haematological malignancies. BI 894999 is a novel oral BET inhibitor that has demonstrated potent antitumour activity in preclinical studies. 1367.1 was an open-label, Phase Ia/Ib dose-finding study evaluating BI 894999 once daily in patients with advanced solid tumours (Schedule A: 0.2, 0.5, 1.0, 1.5, 2.0, and 5.0 mg, Days 1-21/21-d cycle; Schedule B: 1.5, 2.0, and 2.5 mg, Days 1-15/21-d cycle; Schedule C: loading dose 5.0, 6.0, or 7.0 mg on Day 1 followed by maintenance dose 2.5, 3.0, or 3.5 mg, Days 2-7 and 15-21/28-d cycle); 77 patients were enrolled. NCT02516553. Grade ≥3 dose-limiting toxicities (DLTs) were reported in 8/21, 5/25, and 9/31 patients for Schedules A, B, and C, respectively. Thrombocytopenia was reported as a DLT in 28.6%, 4.8%, and 9.7% for Schedules A, B, and C, respectively. Other DLTs occurring in ≥1 patient were troponin T increase (13.6%), hypophosphataemia (4.5%), and elevated creatine phosphokinase (3.0%). Disease control was achieved in 23.8%, 24.0%, and 29.0% of patients for Schedules A, B, and C, respectively. A partial response was achieved in 9.5% and 4% of patients with Schedules A and B, respectively. The best response with Schedule C was stable disease. The 1.5, 2.5, and 6.0/3.0 mg doses in Schedules A, B, and C, respectively, were declared as maximum tolerated dose. Based on the strength of these data, BI 894999 was further evaluated in a Phase Ib trial.


Nephrotic syndrome (NS) and pregnancy in rat--evaluation of kidney in electron microscopy.
The purpose of this study was the histological evaluation of kidneys on the ultrastructural level. In the experiment there were used pregnant female rats in which gestation coexisted with adriamycin-induced NS. Results showed numerous focal changes in kidney glomerules and tubules which were the evidence of increased protein loss and filtration barrier damage as the main cause of increased permeability for proteins.


Human cytosolic sulfotransferase SULT1C4 mediates the sulfation of doxorubicin and epirubicin.
Doxorubicin, an anthracycline, has been reported to be excreted in sulfate conjugated form. The current study aimed to identify the human cytosolic sulfotransferase(s) (SULT(s)) that is(are) capable of sulfating doxorubicin and its analog epirubicin, and to verify whether sulfation of doxorubicin and epirubicin may occur under metabolic conditions. A systematic analysis of thirteen known human SULTs, previously cloned, expressed, and purified, revealed SULT1C4 as the only human SULT capable of sulfating doxorubicin and epirubicin. Cultured HepG2 human hepatoma cells and Caco-2 human colon carcinoma cells were labeled with [(35)S]sulfate in the presence of different concentrations of doxorubicin or epirubicin. Analysis of spent labeling media showed the generation and release of [(35)S]sulfated doxorubicin and epirubicin by HepG2 cells and Caco-2 cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed the expression of SULT1C4 in both HepG2 cells and Caco-2 cells. These results provided a molecular basis underlying the previous finding that sulfate-conjugated doxorubicin was excreted in the urine of patients treated with doxorubicin.


New developments in the etiology and pathogenesis of bacterial vaginosis.
Bacterial vaginosis is unlike the "classic" sexually transmitted diseases. Unlike cervical infection with Chlamydia or salpingitis caused by N. gonorrhoeae, no single etiologic agent has been identified, and the organisms which are associated with infection have all been found as members of endogenous vaginal flora, with the possible exception of Mobiluncus species. If, as we suspect, BV is due to interactions among various organisms found in the vagina during vaginal health, we must determine what changes in the microbial or chemical ecology determine the development of BV. If, for instance, BV is simply due to an inversion in the concentrations of various organisms such that the anaerobes which are usually present in low numbers become predominant and the lactobacilli which usually predominate become few in number, we must determine which causes what. That is, does some organism or environmental change allow the anaerobes to overgrow and thereby inhibit the lactobacilli, or does some change inhibit the lactobacilli, thereby, allowing the other flora to overgrow? Answers to questions such as these await further research.


Transition to frailty in older Japanese people during the coronavirus disease 2019 pandemic: a prospective cohort study.
Globally, lifestyles have changed to prevent the spread of coronavirus disease 2019 (COVID-19). Therefore, we aimed to understand health and lifestyle conditions associated with frailty transition over 6 months and devise a method for identifying frailty among community-dwelling older people during the COVID-19 pandemic. This community-based prospective cohort study was conducted from May to July 2020 (baseline) and November 2020 to January 2021 (follow-up) in Japan, with 1,953 community-dwelling older people (≥65 years) at baseline. To identify transition from non-frailty at baseline to frailty at follow-up, the Frailty Screening Index was used. For predicting frailty transition, two self-reported questionnaires assessing health and lifestyle conditions were employed. Overall, 706 individuals returned the baseline and follow-up questionnaires. Among the 492 non-frail older people at baseline, there was a 9.8% increase in frailty transition. The adjusted model for frailty transition by age, sex, multimorbidity, and living arrangements indicated that forgetfulness (odds ratio [OR] 2.74, 95% confidence interval [CI]: 1.00 to 7.51), falls in the past year (OR 2.26, 95% CI: 1.08 to 4.74), and subjective leg muscle weakness (OR 1.83, 95% CI: 1.05 to 3.21) were predictors of frailty transition. The combination of age ≥75 years and subjective leg muscle weakness showed moderate sensitivity, specificity, and % accuracy (0.688, 0.696, and 69.5%, respectively). Approximately 10% of older people showed new transitions to frailty over 6 months during the COVID-19 pandemic. A combination of age and subjective leg muscle weakness is a feasible measure to optimally identify frailty transition.


Low Rates of Antifungal Therapeutic Drug Monitoring Among Inpatients Who Received Itraconazole, Posaconazole, or Voriconazole, United States, 2019-2021.
Antifungal therapeutic drug monitoring (TDM) is recommended for hospitalized patients receiving itraconazole, posaconazole, or voriconazole for treatment or prophylaxis. In this analysis of hospital-based data, TDM was uncommonly performed (15.8%) in a large cohort of eligible patients, suggesting missed opportunities to avoid subtherapeutic drug levels and minimize toxicity.


Partial status epilepticus associated with asomatognosia and alien hand-like behaviors [corrected].
Paroxysmal alien hand syndrome (AHS) has been reported in association with ictal phenomena, but simultaneous electroencephalographic verification has not been made. A 61-year-old woman with a right hemisphere glioblastoma multiforme developed movements of the left hand that she claimed were not under her control, and she denied ownership of the affected limb. Simultaneous electroencephalograms documented continuous spikes in the right frontotemporal region. Intravenous diazepam therapy (2.5 mg) reversed both the abnormal movements and the spike activity on the electroencephalograms. Our case demonstrates that partial seizures can produce AHS along with asomatognosia. This variety of AHS appears to be different, both etiologically and phenomenologically, from other forms of AHS.