Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression.
Reactive oxygen species (ROS) and subsequent oxidative damage may contribute to the formation and persistence of multiple sclerosis (MS) lesions by acting on distinct pathological processes. ROS initiate lesion formation by inducing blood-brain barrier disruption, enhance leukocyte migration and myelin phagocytosis, and contribute to lesion persistence by mediating cellular damage to essential biological macromolecules of vulnerable CNS cells. Relatively little is known about which CNS cell types are affected by oxidative injury in MS lesions. Here, we show the presence of extensive oxidative damage to proteins, lipids, and nucleotides occurring in active demyelinating MS lesions, predominantly in reactive astrocytes and myelin-laden macrophages. Oxidative stress can be counteracted by endogenous antioxidant enzymes that confer protection against oxidative damage. Here, we show that antioxidant enzymes, including superoxide dismutase 1 and 2, catalase, and heme oxygenase 1, are markedly upregulated in active demyelinating MS lesions compared to normal-appearing white matter and white matter tissue from nonneurological control brains. Particularly, hypertrophic astrocytes and myelin-laden macrophages expressed an array of antioxidant enzymes. Enhanced antioxidant enzyme production in inflammatory MS lesions may reflect an adaptive defense mechanism to reduce ROS-induced cellular damage.


Aortic calcified particles modulate valvular endothelial and interstitial cells.
Normal and calcified human valve cusps, coronary arteries, and aortae harbor spherical calcium phosphate microparticles of identical composition and crystallinity, and their role remains unknown. The objective was to examine the direct effects of isolated calcified particles on human valvular cells. Calcified particles were isolated from healthy and diseased aortae, characterized, quantitated, and applied to valvular endothelial cells (VECs) and interstitial cells (VICs). Cell differentiation, viability, and proliferation were analyzed. Particles were heterogeneous, differing in size and shape, and were crystallized as calcium phosphate. Diseased donors had significantly more calcified particles compared to healthy donors (P<.05), but there were no differences between the composition of the particles from healthy and diseased donors. VECs treated with calcified particles showed a significant decrease in CD31 and VE-cadherin and an increase in von Willebrand factor expression, P<.05. There were significantly increased α-SMA and osteopontin in treated VICs (P<.05), significantly decreased VEC and VIC viability (P<.05), and significantly increased number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive VECs (P<.05) indicating apoptosis when treated with the calcified particles. Isolated calcified particles from human aortae are not innocent bystanders but induce a phenotypical and pathological change of VECs and VICs characteristic of activated and pathological cells. Therapy tailored to reduce these calcified particles should be investigated.


Esterases of earthworms--III. Electrophoresis reveals that Eisenia fetida (Savigny) is two species.
Polyacrylamide gel electrophoresis of esterases in earthworms classified as Eisenia fetida (Savigny) revealed the existence of two species. The classification based upon esterase electromorphs coincided with classification into two colour variants formerly described as subspecies under the names E. fetida typica and E. fetida unicolor (André, 1963). Two main groups of esterases, acetylesterases and carboxylesterases were found. Because of less variability within species and higher stability the acetylesterases are regarded as the most useful in taxonomy. Sterile hybrids, with hybrid esterase patterns were produced at a low rate in the laboratory, but were never found with certainty in the wild populations. Eisenia fetida (Savigny) and Eisenia unicolor (André) are the names proposed for the two species.


The number of activating KIR genes inversely correlates with the rate of CMV infection/reactivation in kidney transplant recipients.
Viral infection is a common complication after kidney transplantation. The role of natural killer cells (NK cells) in this setting remains unknown. NK cells express activating and inhibitory killer cell immunoglobulin-like receptors (KIR). We analyzed whether activating KIR genes carried by kidney transplant-recipients influence the rate of viral infection during the first year after transplantation. In patients with a KIR A/A genotype (n = 40, KIR2DS4 only activating KIR) the rate of cytomegalovirus (CMV) infection and reactivation was 36%, as compared to 20% in transplant recipients with more than one activating KIR gene (KIR B/X genotype, n = 82, p = 0.04). Adjusting for other risk factors in Cox regression, the relative risk of B versus A genotype patients was 0.34 (95% CI 0.15-0.76, p = 0.009). The degree of protection increased with the number of activating KIR genes. Symptomatic CMV disease was only observed in four individuals, all carrying a KIR A/A genotype. As for viral infections other than CMV, and for bacterial infections, no KIR-linked protective effect could be detected. Also, graft function and the rate-rejection episodes were similar in KIR A/A and KIR B/X genotype individuals. This study supports a role for activating KIR in the control of CMV infection after kidney transplantation.


Exposure to screens during meals in infants with functional gastrointestinal disorders.
Since meals are a special moment in the parent-infant relationship and functional gastrointestinal disorders (FGD) are frequent in infants, this study mainly aimed to describe the frequency of exposure to screens during meals in infants with FGD. This French non-interventional, cross-sectional, and multicenter study was conducted with FGD infants (aged 1-12 months), consecutively included by private pediatricians and general practitioners. Descriptive analysis was performed. Data from 816 infants, included by 246 physicians, were analyzed: mean age: 4.8 ± 2.9 months; FGD: regurgitation (81%), colic (61%), constipation (30%), and/or diarrhea (12%). Overall, 465 infants (57.0%, 95% CI [45.6%-60.4%]) were regularly exposed to screens during meals. Of these exposed infants, 131 (28.2%, 95% CI [24.1%-32.3%]) were directly exposed. Explicative factors of the overall screen exposure during meals were the following: >2 children in the household (p = 0.0112), infant meals in the living room (p < 0.0001) or the dining room (p = 0.0001), and mother or father being blue-collar workers, white-collar workers, or without employment (mother: p = 0.0402; father: p = 0.0375). This real-world French study showed the high proportion of FGD infants under 12 months of age who are exposed to screens during meals. Our data suggest that information to parents on the potential adverse effects of screen exposure should be reinforced, including for infants.


Structure and sequence of the multihaem cytochrome c3.
The molecular structure of cytochrome c3 isolated from Desulfovibrio desulfuricans has been solved on the basis of its crystallographic determination at 2.5 A resolution and of an essentially complete sequence. The molecule consists of a single polypeptide chain wrapped around a very compact core of four non-parallel haems which present a relatively high degree of exposure to the solvent. Alignment of the amino acid sequences of cytochrome c3 from several species suggests that the structure reported here is characteristic of the cytochrome c3 group.


Benign nodules of the thyroid gland and 25-hydroxy-vitamin D levels in euthyroid patients.
The presence of nodules in the thyroid gland is common in iodine-deficient areas of the world. Recently, vitamin D levels were found to be lower than normal and sometimes deficient in malignant nodules of the thyroid. Evaluate the relationship between the serum vitamin D levels and benign thyroid nodules in euthyroid patients. Cross-sectional. Tertiary care center in Turkey. Patients referred to the general surgery outpatient clinic and diagnosed with thyroid nodules were the study group. The control group consisted of healthy individuals without thyroid nodules. Age, BMI, thyroid ultrasonography, serum 25-hydroxyvitamin D, free T3, free T4, thyroid stimulating hormone, calcium, magnesium, phosphorous, total protein, albumin, glucose, creatinine levels and glomerular filtration rate (GFR) were compared between groups. Serum 25-hydroxy-vitamin D levels and size of the thyroid nodules. Of 849 individuals, 453 were patients with thyroid nodules and 396 were healthy individuals. The mean serum vitamin D levels of patients with thyroid nodules were significantly lower than controls (P<.001). Serum vitamin D levels along with serum total protein levels and eGFR were independent variables associated with the presence of a thyroid nodule (P<.001, p=.005 and P=.017, respectively). These findings suggest vitamin D deficiency might be one of the pathophysiologic factors in development of thyroid nodules. Single-center and possible information bias. None.


A survey to investigate movements off sheep and cattle farms in New Zealand, with reference to the potential transmission of foot-and-mouth disease.
To quantify the numbers and extent of movements off sheep and cattle farms in New Zealand, in order to construct more realistic simulation models to investigate how infectious diseases such as foot-and-mouth disease (FMD) might spread. Farmers from 500 randomly selected farms, comprising 100 from each of the following sectors, viz beef, dairy, grazing/dairy heifer rearing, sheep, and mixed sheep and beef, were asked to fill in diaries in which they recorded the movements of all animals, products, people, vehicles and equipment coming on to or leaving their farms during two separate 3-week periods, representing relatively 'busy' and 'quiet' times of the year with respect to livestock movements. Where possible, the destination of each movement was identified and geo-coded, to allow the distance travelled to be calculated. Each movement was then classified according to the risk of transfer of FMD virus (FMDV), should the disease have been present on the study farm at the time of the movement. The data were then analysed to establish movement frequencies and distributions of distances travelled, by the different pastoral livestock sectors. Two hundred and seventeen farmers returned one or more diaries. One hundred and ninety-three farmers completed a Busy-period diary, recording a total of 12,052 movements off their farms, a crude average of 62.4 per 3-week period, or 2.97 per day. Of these, 4.0% involved the transport of livestock, equating to 0.12 livestock consignments per day. In contrast, 186 Quiet-period diaries were returned, recording a total of 10,885 movements off, representing a crude average of 58.5 during the 3-week period, or 2.78 per day. Of these, 2.1% involved livestock, equating to 0.06 livestock consignments per day. The mean and median distances travelled during the Busy periods were 30.9 km and 13.1 km, respectively (range 0-1,167 km). In comparison, the mean and median distances travelled during Quiet periods were 41.3 and 14 km, respectively (range 0.4-1,203 km). People, vehicles, livestock and other items can travel off pastoral livestock farms in New Zealand to other farms either directly or via saleyards over extensive distances. This has implications for the potential spread of infectious diseases such as FMD. Movement parameters intended for use in the InterSpread Plus inter-farm simulation model of FMD were established, which will facilitate the prediction of likely spread and efficacy of controls in the unlikely event of a real-life outbreak.


Fragile sites, chromosome evolution, and human neoplasia.
In a study of the possible relationship between human fragile sites, chromosomal rearrangements related to neoplasia, and chromosome regions involved in evolutionary changes, we have found that 17 fragile sites related to cancer, 15 fragile sites not related to cancer, and 17 non-fragile regions also related to human malignancy correspond or are close to bands involved in rearrangements that have taken place during chromosomal evolution in primates.


Intestinal spirochetes isolated from wild-living jackdaws, hooded crows and rooks (genus Corvus): provisionally designated "Brachyspira corvi" sp. nov.
Intestinal spirochetes of genus Brachyspira are commonly isolated from mammalian and avian hosts, and several species have been reported to cause enteric disease in pigs and birds. Except for a previous publication on three isolates from corvid birds (order Passeriformes, family Corvidae, genus Corvus), of which two are further studied in this paper, no other reports exist on Brachyspira spp. of passerine birds. In this study, cloacal and intestinal swabs of small and large intestines were collected from 116 corvid birds of three species, i.e. jackdaws (Corvus monedula), hooded crows (Corvus corone cornix) and rooks (Corvus frugilegus), from four separate geographical locations in Sweden. Isolates were obtained by selective culture from 43 of 116 birds. All isolates were weakly hemolytic, indole-negative and lacked hippurate cleavage capacity. Examination by light microscopy did not indicate association with enteric disease in necropsied birds. Pure spirochete cultures were obtained by serial dilution and subculture, and selected isolates were analyzed by PCR (n=14), randomly amplified polymorphic DNA (RAPD) (n=14), and sequencing of the almost complete 16S rRNA (n=14), and partial nox genes (n=4). Positive reactions were noticed by PCR targeting a hexa-T segment of the 16S rRNA gene, which has been previously reported as a signature characteristic of Brachyspira pilosicoli. By 16S rRNA gene sequencing, the isolates formed a separate cluster related to genus Brachyspira, but not consistent with any presently recognized or proposed Brachyspira sp. The sequence similarity of the 16S rRNA gene among the isolates from corvid birds was 99.7-100%. Compared to 16S rRNA gene sequence data from all presently recognized and several proposed Brachyspira spp. the sequence similarity of the isolates from corvid birds varied between 94.1 and 96.5%. In a radial tree based on nox gene sequences, all four analyzed isolates from corvid birds formed a separate cluster. By RAPD analysis, the banding patterns of the isolates differed from all type strains of Brachyspira spp. Based on the results presented in this paper, we propose that the described isolates from corvid birds belong to a novel species within genus Brachyspira, with the provisional name "Brachyspira corvi" (cor'vi. L gen. n. corvi, of a crow).


Lung abscess and empyema following bronchoscopy: A case report and review of the literature.
Severe pulmonary infections after bronchoscopy and transbronchial lung biopsy (TBLB) are uncommon. We report a rare case of lung abscess and empyema after a routine TBLB performed for the diagnosis of lung cancer.


Use of Specific Duodenal Dose Constraints During Treatment Planning Reduces Toxicity After Definitive Paraaortic Radiation Therapy for Cervical Cancer.
This study aimed to validate the safety of paraaortic nodal (PAN) radiation therapy (RT) for patients with cervical cancer when the duodenal dose is limited to V55 < 15 cm3 and V60 < 2 cm3. A total of 97 patients who were treated with RT for cervical cancer between 2010 and 2018 received at least 56 Gy to grossly involved PANs. Patients were treated with concurrent chemoradiation (n = 88; 91%), with 93% of patients (n = 90) receiving intensity modulated RT to the initial PAN field and 98% (n = 95) receiving intensity modulated RT to a sequential PAN boost. The V55 < 15 cm3 and V60 <2 cm3 criteria were implemented in 2014. Normal tissues were contoured on computed tomography (CT) simulation data sets, and the duodenum was contoured from the gastric outlet to the duodenojejunal flexure. Sixty-six patients (68%) had a resimulation scan after approximately 20 fractions. Composite duodenal doses were calculated using the initial CT scan for 50 patients (52%) and the resimulation CT scan for 47 patients (48%) depending on the anatomic changes throughout treatment. The median duodenal V55 was 3.5 cm3 (interquartile range [IQR], 0.2-8.1 cm3) and the median V60 was 0.3 cm3 (IQR, 0.0-1.8). Constraints were exceeded in 18 patients, of whom 16 patients (89%) had been treated before 2014. Treatment for the 2 patients treated after 2014 was complicated by significant weight loss and reduced anterior-posterior diameter, which likely overestimated the true dose on the composite plan. Only 1 patient experienced grade 3 duodenal toxicity (stricture requiring endoscopic balloon dilation 3 months after treatment); however, the stricture was outside of the high-dose boost volume, and the patient had a history of gastritis. Six patients (6%) had a first recurrence within the PAN region. Limiting the duodenal dose to V55 < 15 cm3 and V60 < 2 cm3 for patients with cervical cancer and PAN involvement is feasible, and minimizes duodenal toxicity while maintaining acceptable local control rates.


Midtrimester cervical elastography in pregnant women with a history of loop electrosurgical excision procedure (LEEP).
We aimed to compare cervical elastographic parameters based on a previous loop electrosurgical excision procedure (LEEP) and to determine whether they can predict preterm delivery in pregnant women with a history of LEEP. This multicenter prospective case-control study included 71 singleton pregnant women at 14-24 weeks of gestation with a history of LEEP and 1:2 gestational age-matched controls. We performed cervical elastography using E-cervix and compared maternal characteristics, delivery outcomes, cervical length (CL), and elastographic parameters between the two groups. The median mid-trimester CL was significantly shorter in the LEEP group. Most elastographic parameters, including internal os (IOS), external os (EOS), elasticity contrast index (ECI), and hardness ratio (HR), were significantly different in the two groups. In the LEEP group, the sPTD group compared to the term delivery (TD) group showed a higher rate of previous sPTD (50% vs. 1.7%, p < 0.001), higher IOS and ECI (IOS: 0.28 [0.12-0.37] vs. 0.19 [0.10-0.37], p = 0.029; ECI: 3.89 [1.79-4.86] vs. 2.73 [1.48-5.43], p = 0.019), and lower HR (59.97 [43.88-92.43] vs. 79.06 [36.87-95.40], p = 0.028), but there was no significant difference in CL (2.92 [2.16-3.76] vs. 3.13 [1.50-3.16], p = 0.247). In conclusion, we demonstrated that a history of LEEP was associated with a change in cervical strain measured in mid-trimester as well as with CL shortening. We also showed that cervical elastography can be useful in predicting sPTD in pregnant women with previous LEEP.


Salvage surgery in recurrent sinonasal cancers: Proposal for a prognostic model based on clinicopathologic and treatment-related parameters.
Evidence on survival and major prognosticators after salvage surgery in recurrent sinonasal cancers (SNC) is limited. A retrospective, single-center study of recurrent SNC treated with salvage surgery between 1997 and 2019 was conducted. Univariate and multivariable analyses were performed to define a prognostic score for overall survival (OS). One hundred and eighteen patients were included. Recurrent SNC originated mostly in the naso-ethmoidal box (67.8%) and were mainly epithelial (76.2%), high-grade (49.2%), and locally advanced (rpT4, 60.1%) malignancies. Negative margins were achieved in 56.6% of cases. Two- and 5-year OS were 71.7% and 56%, respectively. The prognostic model included treatment modality for primary tumor, histology, rpT class, margin status, perineural invasion, and adjuvant radiotherapy and stratified patients into three prognostic groups (5-year OS: 84.4%, 44.9%, and 0%, respectively). Treatment of recurrent SNC can result in good long-term survival estimates with limited morbidity. Our score can provide excellent prognostic stratification.


Estimating the number of farms experienced foot and mouth disease outbreaks using capture-recapture methods.
Foot and mouth disease (FMD) is recognized as an endemic disease in Thailand and throughout other countries in Southeast Asia. The underreporting of FMD outbreaks has affected the true status of the disease. This study aimed to determine the number of dairy farms in Chiang Mai that had experienced FMD outbreaks (FMD outbreak farm) during 2015-2016 using capture-recapture (CR) methods. Two independent FMD outbreak data sources including data from the livestock authorities and survey questionnaires were analyzed using Chapman estimator and Chao estimator. Results showed that the estimated number of FMD outbreak farms was 264 (95% CI = 250, 277) and 273 (95% CI = 259, 292) farms based on the Chapman estimator and Chao estimator, respectively. The estimated prevalence of FMD corresponding to the Chapman estimator was lower than the Chao estimator. The active approach of the survey method offered a higher degree of sensitivity compared to the passive method used by the livestock authorities. Estimations from the CR method provided an upper bound for the true number of outbreak farms. This study demonstrated the use of the CR method to estimate the true status of FMD outbreaks. Our proposed approach can potentially be used as a tool to enhance the accuracy and sensitivity of established monitoring and surveillance systems.


Celebrating 80 years anniversary of radioiodine for use in thyroid cancer and perspectives for theranostics.
In 1942, eighty years ago, Dr. Hertz first conducted radioiodine (RAI) diagnosis and therapy for thyroid disorders followed later by the successful treatment of thyroid cancer patients using RAI. In 2022, memorial 80 years later, alpha emitter astatine (211At), an analogue for iodine, was successfully administered to a patient with refractory thyroid cancer in Japan as a phase-1 clinical trial (first-in-human). Over the past two decades, the use of 68 Ga labeled peptides for somatostatin receptor (SSTR)-targeted PET imaging followed by beta or alpha emitters labeled SSTR-analogues for peptide receptor radionuclide therapy (PRRT) has demonstrated remarkable success in the management of neuroendocrine neoplasms. In addition, theranostics targeting prostate-specific membrane antigen (PSMA) have dramatically changed the management and treatment of advanced prostate cancer patients. Novel radionuclides and new targets, ligands targeting the tumor microenvironment, optimized peptides and antibodies, combinations of radioligands with immunotherapy, radioprotectors and radiosensitizers as well as new delivery strategies are currently systematically explored. Now the dream of conquering cancer, that Saul Hertz began eight decades ago is coming to fruition.


The role of electrocardiogram in sex verification in a young adult with primary amenorrhea: a case report.
The use of electrocardiogram for sex verification in adults is an emerging concept in medicine. It is feasible through the utilization of Ogunlade Sex Determination Electrocardiographic Score. The aim of this study was to use an electrocardiogram to verify the sex of a woman with primary amenorrhea. We report a case of a 36-year-old woman of Yoruba ethnicity who presented with primary amenorrhea. A physical examination revealed a woman with a feminine appearance characterized by long plaited hair and well-developed breasts. As part of the investigations to unravel the sex status, she had a resting standard 12-lead electrocardiogram which revealed a masculine electrocardiogram pattern with Ogunlade Sex Determination Electrocardiographic Score of 9 (T-wave pattern in lead V1, 3; ST segment in lead V2 or V3, 3; QRS rotation, 2; heart rate of 79, 1). An abdominopelvic ultrasonography done by a radiologist showed absence of uterus, fallopian tubes, and ovaries. When our patient was considered for transvaginal scan, she declined but embraced translabial ultrasound as she claimed to be a virgin. Translabial ultrasonography revealed the presence of undescended hypoplastic testes with associated testicular microlithiasis at the external inguinal rings bilaterally. Karyotyping using a blood sample revealed 46,XY and a sex-determining region Y report showed that the blood sample was positive for the SRY gene confirming the status as male. This synchronized with the initial electrocardiogram evaluation. The testes were later removed. This report concluded that an electrocardiogram as a cheap, readily available and non-invasive test has a role in sex verification in young adults with primary amenorrhea.


A randomized, double-blind, placebo-controlled pilot study to assess the effects of protopanaxadiol saponin-enriched ginseng extract and pectinase-processed ginseng extract on the prevention of acute respiratory illness in healthy people.
GS-3K8 and GINST, both of which are modified ginseng extracts, have never been examined in terms of their effectiveness for the prevention of acute respiratory illness (ARI) in humans. We conducted a pilot study to assess the feasibility of performing a large-scale, randomized, controlled trial. This study was a randomized, double-blind, placebo-controlled, pilot study at a single center from October 2014 to March 2015. The 45 healthy applicants were randomly divided into the GS-3K8 (n = 15), GINST (n = 15), and placebo groups (n = 15). The study drug was administered as a capsule (500 mg/cap and 3000 mg/day). GS-3K8 contained 6.31 mg/g of Rg1, 15.05 mg/g of Re, 30.84 mg/g of Rb1, 15.02 mg/g of Rc, 12.44 mg/g of Rb2, 6.97 mg/g of Rd, 1.59 mg/g of Rg3, 3.25 mg/g of Rk1, and 4.84 mg/g of Rg5. GINST contained 7.54 mg/g of Rg1, 1.87 mg/g of Re, 5.42 mg/g of Rb1, 0.29 mg/g of Rc, 0.36 mg/g of Rb2, 0.70 mg/g of Rd, and 6.3 mg/g of compound K. The feasibility criteria were the rates of recruitment, drug compliance, and successful follow-up. The primary clinical outcome measure was the incidence of ARI. The secondary clinical outcome measures were the duration of symptoms. The rate of recruitment was 11.3 participants per week. The overall rate of completed follow-up was 97.8%. The mean compliance rate was 91.64 ± 9.80%, 95.28 ± 5.75%, and 89.70 ± 8.99% in the GS-3K8, GINST, and placebo groups, respectively. The incidence of ARI was 64.3% (9/14; 95% confidence interval [CI], 31.4-91.1%), 26.7% (4/15; 95% CI, 4.3-49.0%), and 80.0% (12/15; 95% CI, 54.8-93.0%) in the GS-3K8, GINST, and placebo groups, respectively. The average days of symptoms were 3.89 ± 4.65, 9.25 ± 7.63, and 12.25 ± 12.69 in the GS-3K8, GINST, and placebo groups, respectively. The results support the feasibility of a full-scale trial. GS-3K8 and GINST appear to have a positive tendency toward preventing the development of ARI and reducing the symptom duration. A randomized controlled trial is needed to confirm these findings.


Adolescent health care: perceptions and needs of the practicing physician.
Three hundred thirty-one Indiana physicians practicing general-family medicine (GP-FP), obstetrics-gynecology (OB-GYN), pediatrics (PED), internal medicine (IM), and psychiatry (PSYCH) were surveyed as to their perceptions about adolescent health and their perceived need for specific adolescent services and Continuing Medical Education (CME). Significant differences were noted in all specialty areas that were not accounted for by the sex or age of the physician. The majority of GP-FP and PED reported that adolescents (aged 11-19 years) made up at least 10% of their practice compared to fewer than 5% of IM practices. Fewer than 7% of the respondents had had no training about adolescent medicine; most (47.5%) had received some CME in adolescent medicine. Family planning was the service least likely to be: provided by PED, IM, and PSYCH, (p less than 0.0001); considered serious for these physicians' adolescent patients (p less than 0.0001); and of interest for CME by all physicians (p less than 0.0001). All specialities believed their adolescent patients to be minimally troubled by the most common problems of youth (p less than 0.0001), but did accurately perceive youth as having psychosocial and medical problems. Training about substance abuse, counseling, learning problems, and eating disorders were most desired. Few respondents wanted individualized, in-person training. The implications of these results are discussed.


Observations on the spawning behavior, egg masses and paralarval development of the ommastrephid squid Todarodes pacificus in a laboratory mesocosm.
The spawning behavior of ommastrephid squids has never been observed under natural conditions. Previous laboratory observations of Japanese flying squid (Todarodes pacificus) suggest that pre-spawning females might rest on the continental shelf or slope before they ascend above the pycnocline to spawn, and that the egg masses might settle in the pycnocline. Here, two mesocosm experiments were conducted in a 300 m(3) tank that was 6 m deep to investigate this hypothesis. In the first experiment, a thermocline (2.5-3.5 m) was established in the tank by creating a thermally stratified (17-22°C) water column. In the second experiment, the temperature was uniform (22°C) at all depths. Prior to spawning, females did not rest on the tank floor. In the stratified water column, egg masses remained suspended in the thermocline, but in an unstratified water column, they settled on the tank bottom, collapsed and were infested by microbes, resulting in abnormal or nonviable embryos. Eleven females spawned a total of 18 egg masses (17-80 cm in diameter), indicating that females can spawn more than once when under stress. Paralarvae hatched at stage 30/31 and survived for up to 10 days, allowing us to observe the most advanced stage of paralarvae in captivity. Paralarvae survived after consumption of the inner yolk, suggesting they might have fed in the tank.


LUNG CANCER AND PULMONARY THROMBOEMBOLISM.
Malignant diseases including lung cancer are the risk for development of pulmonary thromboembolism (PTE). To show the number of PTE in patients with lung cancer treated in Clinic for pulmonary diseases and TB "Podhrastovi" in three-year period: from 2012-2014. This is the retrospective study in which we present the number of various types of lung cancer treated in three-year period, number and per cent of PTE in different types of lung carcinoma, number and per cent of PTE of all diagnosed PTE in lung carcinoma according to the type of carcinoma. In three-year period (from 2012 to 2014) 1609 patients with lung cancer were treated in Clinic for pulmonary diseases and TB "Podhrastovi" Clinical Centre of Sarajevo University. 42 patients: 25 men middle -aged 64.4 years and 17 women middle- aged 66.7 or 2.61% of all patients with lung cancer had diagnosed PTE. That was the 16. 7% of all patients with PTE treated in Clinic "Podhrastovi "in that three-year period. Of all 42 patients with lung cancer and diagnosed PTE 3 patients (7.14%) had planocellular cancer, 4 patients (9.53%) had squamocellular cancer, 9 (21.43%) had adenocarcinoma, 1 (2.38%) had NSCLC, 3 (7.14 %) had microcellular cancer, 1 (2.38%) had neuroendocrine cancer, 2 (4.76%) had large cell-macrocellular and 19 (45.24%) had histological non-differentiated lung carcinoma. Malignant diseases, including lung cancer, are the risk factor for development of PTE. It is important to consider the including anticoagulant prophylaxis in these patients and so to slow down the course of diseases in these patients.


Bupivacaine 0.01% and/or epinephrine 0.5 microg/ml improve epidural fentanyl analgesia after cesarean section.
The authors studied the addition of bupivacaine and epinephrine, separately and together, to epidural fentanyl to determine whether this improved postcesarean analgesia and reduced the incidence of side effects. After elective cesarean section, 100 parturient patients who received fentanyl (3 microg/ml) epidurally for 48 h were allocated randomly in a double-blinded manner to four groups to receive, in addition to the study solution, 0.01% bupivacaine, 0.5 microg/ml epinephrine, both, or neither. A neurologic assessment of breast-fed neonates was made at 2 and 48 h of life. Plasma fentanyl concentrations were determined in a subset of patients at intervals after treatment. Patients receiving fentanyl alone made more attempts at patient-controlled analgesia (P < 0.01), required a greater total dose of fentanyl (P < 0.01), reported more pain (P < 0.003) and less satisfaction (P < 0.003), and had more nausea and urinary retention (P < 0.05) than all other groups. Patients who received bupivacaine with or without epinephrine had better overall satisfaction scores than those who did not receive bupivacaine (P < 0.001), and they required less fentanyl (P < 0.02) than patients who received fentanyl with only epinephrine. Motor blockade or orthostatic hypotension did not develop in any patient, and all patients could ambulate without difficulty. Neurobehavioral scores, which were similar among all neonates, were within the normal range. Plasma concentrations of fentanyl increased after epinephrine-containing solutions were discontinued. During the conditions of this study, the addition of epinephrine and bupivacaine to a 3-microg/ml epidural fentanyl solution for postcesarean section pain relief provided superior analgesia compared with fentanyl alone or fentanyl with epinephrine. Whether increasing the concentration of fentanyl alone might improve the efficacy of fentanyl remains unclear.


Semaphorin 3G exacerbates joint inflammation through the accumulation and proliferation of macrophages in the synovium.
Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA). However, the precise mechanisms by which MTX stalls RA progression and alleviates the ensuing disease effects remain unknown. The aim of the present study was to identify novel therapeutic target molecules, the expression patterns of which are affected by MTX in patients with RA. CD4+ T cells from 28 treatment-naïve patients with RA before and 3 months after the initiation of MTX treatment were subjected to DNA microarray analyses. The expression levels of semaphorin 3G, a differentially expressed gene, and its receptor, neuropilin-2, were evaluated in the RA synovium and collagen-induced arthritis synovium. Collagen-induced arthritis and collagen antibody-induced arthritis were induced in semaphorin3G-deficient mice and control mice, and the clinical score, histological score, and serum cytokines were assessed. The migration and proliferation of semaphorin 3G-stimulated bone marrow-derived macrophages were analyzed in vitro. The effect of local semaphorin 3G administration on the clinical score and number of infiltrating macrophages during collagen antibody-induced arthritis was evaluated. Semaphorin 3G expression in CD4+ T cells was downregulated by MTX treatment in RA patients. It was determined that semaphorin 3G is expressed in RA but not in the osteoarthritis synovium; its receptor neuropilin-2 is primarily expressed on activated macrophages. Semaphorin3G deficiency ameliorated collagen-induced arthritis and collagen antibody-induced arthritis. Semaphorin 3G stimulation enhanced the migration and proliferation of bone marrow-derived macrophages. Local administration of semaphorin 3G deteriorated collagen antibody-induced arthritis and increased the number of infiltrating macrophages. Upregulation of semaphorin 3G in the RA synovium is a novel mechanism that exacerbates joint inflammation, leading to further deterioration, through macrophage accumulation.


Different antigen ratio in bivalent vaccine can affect immunological activation and protection against Aeromonas salmonicida and Vibrio anguillarum in Atlantic salmon.
To effectively prevent the outbreak of furunculosis and vibriosis in Atlantic salmon culture in northern China, the immunological properties and efficacies of bivalent inactivated vaccines composed of two local pathogenic strains, Aeromonas salmonicida C4 and Vibrio anguillarum M3, was analyzed in salmon. The effect of formalin-inactivated A. salmonicida C4, V. anguillarum M3, and their combined vaccines with different antigen ratio of 1:1, 1:2 and 2:1 on relative percentage of survival (RPS), specific antibody production and expression of immune-related genes of fish were investigated. It was found that both C4 and M3 antigen had adjuvant effects on each other's vaccines. Furthermore, the proportion of antigens in the combined vaccines had significantly different effects on immune response and protection against A. salmonicida or V. anguillarum infection. Compared with other vaccinated groups, the C4:M3 = 1:2 vaccine group had the highest immunological activation ability and best immune protection against A. salmonicida and V. anguillarum. Our studies suggest that the development of new multivalent vaccines should carefully design the ratio of different antigens in according to their immunological properties to achieve efficient protection and avoid inhibitory effects of antigens on specific pathogen.


Environmental stress and Umbilicaria lichens: The effect of subzero temperature pretreatments.
Five species of Umbilicaria were used in experiments to determine the effect of moderately below zero temperature pretreatments. Both air-dry and fully-imbibed plants were exposed to-25° C for nine months. The experiments were conducted using samples collected in midsummer and mid-winter. The gas exchange activity of the plants was measured following the low temperature stress, and was compared to the response of unstressed plants. A four-light-level by three-temperature-assay of net CO2 exchange was used throughout. The results showed that exposure of dry plants to-25° C has few effects, but that exposure when imbibed produces a range in response from serious damage to apparent stimulation. For all species the results are consistent with what would be expected knowing the extent and duration of the snow cover is the natural habitat.


Nanophthalmic sclera. Fibronectin studies.
The authors performed fibronectin studies on scleral specimens derived from a patient with nanophthalmos. Immunohistochemical staining with antifibronectin was conducted using both formaldehyde-fixed, paraffin-embedded tissue sections and unfixed tissue-cultured scleral cells. In each case, the nanophthalmic samples exhibited fibronectin staining stronger than that obtained from normal human subjects. Results from an enzyme-linked immunosorbent assay (ELISA) confirmed the histologic findings that, in tissue culture, the patient's scleral cells contained and secreted a higher amount of fibronectin than did the normal control cells. The elevated fibronectin level may be related to the development of nanophthalmos.


Early primary repair of tetralogy of Fallot.
Young age, low weight, and the requirement for transannular patch reconstruction of the right ventricular outflow tract (RVOT) are thought to adversely affect intracardiac repair of tetralogy of Fallot. Forty patients underwent complete repair between January, 1984, and January, 1987. Only infants with pulmonary atresia, complete atrioventricular canal, or coronary artery anomalies were shunted initially. The malalignment ventricular septal defect was closed with a Dacron patch. Infundibular resection was minimized. All atrial communications were left open. Thirty-four patients (85%) had a transannular RVOT patch, and 2 patients (5%) had a nontransannular patch. All 10 infants weighing 3.4 to 9.6 kg had a transannular RVOT patch at 7 weeks to 12 months of age. An RVOT patch was used in 26 of 30 children operated on between 1 and 6 years of age (median age, 24 months). No patient undergoing intracardiac repair died. Postoperative RVOT pullback gradients were between 0 and 35 mm Hg (mean, 18.5 mm Hg). Postoperative pulmonary artery saturation (mean, 73%) did not reveal any residual ventricular septal defect. The right ventricular/arterial pressure ratio was always less than 0.6 (mean, 0.4). All children are doing well at follow-up from two to 37 months. Serial echocardiograms reveal no residual ventricular septal defect and only 1 moderate RVOT gradient. Follow-up cardiac catheterization in 15 patients revealed no residual ventricular septal defect and RVOT gradients between 5 and 35 mm Hg. The right ventricular/left ventricular pressure ratio was always less than 0.6 (mean, 0.48). The early and late results justify continued primary repair of tetralogy of Fallot in symptomatic children, regardless of age or weight.(ABSTRACT TRUNCATED AT 250 WORDS)


Induction of ferroptosis using functionalized iron-based nanoparticles for anti-cancer therapy.
Ferroptosis, a cell death pathway that is induced in response to iron, has recently attracted remarkable attention given its emerging therapeutic potential in cancer cells. The need for a promising modality to improve chemotherapy's efficacy through this pathway has been urgent in recent years, and this non-apoptotic cell death pathway accumulates reactive oxygen species (ROS) and is subsequently involved in lipid peroxidation. Here, we report cancer-targeting nanoparticles that possess highly efficient cancer-targeting ability and minimal systemic toxicity, thereby leading to ferroptosis. To overcome the limit of actual clinical application, which is the ultimate goal due to safety issues, we designed safe nanoparticles that can be applied clinically. Nanoparticles containing ferroptosis-dependent iron and FDA-approved hyaluronic acid (FHA NPs) are fabricated by controlling physicochemical properties, and the FHA NPs specifically induce ROS production and lipid peroxidation in cancer cells without affecting normal cells. The excellent in vivo anti-tumor therapeutic effect of FHA NPs was confirmed in the A549 tumor-bearing mice model, indicating that the induction of FHA NP-mediated cell death via the ferroptosis pathway could serve as a powerful platform in anticancer therapy. We believe that this newly proposed FHA NP-induced ferroptosis strategy is a promising system that offers the potential for efficient cancer treatment and provides insight into the safe design of nanomedicines for clinical applications.


Interleukin-6/soluble interleukin-6 receptor complex reduces infarct size via inhibiting myocardial apoptosis.
Apoptosis of cardiomyocytes plays an important role in reperfusion injury following myocardial infarction. Conversely, interleukin-6 (IL-6)--a potent cytokine--inhibits myeloma cell apoptosis by activating GP130 through the IL-6 receptor (IL-6R). We hypothesized that the IL-6/soluble IL-6R complex can inhibit myocardial apoptosis, and limit infarct size in reperfused acute myocardial infarction. Anesthetized rats were randomly divided into five groups: sham, coronary occlusion and reperfusion rats administered IL-6/soluble IL-6R complex, IL-6 alone, soluble IL-6R (sIL-6R) alone, or a control vehicle. Rats were subjected to 30 min occlusion of the left coronary artery followed by 3 h reperfusion. After reperfusion, the hearts were excised. For detection and quantification of apoptosis, gel electrophoresis of extracted genomic DNA and TUNEL method of paraffin sections were performed. The percentage of the infarct area was measured using tetrazolium chloride staining. The cardiomyocyte apoptosis analysis revealed that apoptosis in the reperfused myocardium was inhibited only in the complex group. Furthermore, the percentage of the infarct area out of the area at risk was remarkably reduced in the complex group (23.8+/-1.8%), compared with that in the vehicle (37.9+/-3.7%), the IL-6 (40.7+/-1.0%), or the sIL-6R (37.5+/-2.4%) groups (P=0.0002). No significant differences were observed among the vehicle, IL-6, and sIL-6R groups. The IL-6/soluble IL-6 receptor complex inhibits cardiomyocyte apoptosis in reperfused acute myocardial infarction. It possibly reduces irreversible reperfusion injury.


Psychosexual material in the stories told by children: the fucker.
The spontaneously reported narrative fictions collected from 5- to 11-year-old children were examined for the presence of overt psychosexual elements. Two developmental hypotheses were advanced: (1) that the children's expressions would become more inhibited and therefore more indirect with age (Wolfenstein) and (2) that their expressions would not be more inhibited with age but simply more complex and wide ranging (Legman). The data are interpreted as supporting the latter proposition. The older children in the present sample give a wide-ranging display of psychosexual material stated just as directly as is the case with the narrower array for the younger children. Freud's dictum that the higher a joke rises in polite society the more indirect must be its form of expression is thus not supported in the present elementary school. The cultural relativity of the hypothesis is suggested. A folktale analysis of these materials shows that they are most appropriately described as typical of the "trickster" figure in folkloric genre. The Fucker appears to be a subcategory of this genre as well as an enduring folk figure.


Patient perspectives on fluticasone-vilanterol versus other corticosteroid combination products for the treatment of asthma.
Fluticasone furoate (FF), an inhaled corticosteroid (ICS), and vilanterol (VI), a long-acting beta2 receptor agonist (LABA), is a new combination used in an Ellipta(®) device. This article compares FF-VI to other ICS-LABA combinations available, particularly emphasizing product selection from the patient perspective. A PubMED and EMBASE search completed in October 2015 identified trials using the MeSH terms "fluticasone", "vilanterol", and "asthma". Additional information was gathered from references cited in the identified publications, the manufacturer, package insert, and ClinicalTrials.gov registry. Preference was given to randomized controlled clinical trials. Animal trials, trials for COPD, and non-English sources were excluded. Seven efficacy trials of FF-VI in asthma were identified. Only one (24 weeks) trial compared FF-VI to another ICS-LABA combination (fluticasone propionate-salmeterol). Primary outcomes (usually lung function) and secondary outcomes (eg, quality of life and symptom scores) were comparable. In three FF-VI safety trials, the type and frequency of common adverse reactions (ie, thrush and dysphonia) were similar to those in clinical trials. Over 90% of subjects rated the Ellipta(®) device as "easy to use" and demonstrated correct device technique initially and at 4 weeks. Individuals may have drug- and device-specific preferences that should be incorporated into therapeutic decision making. Limited data indicate that clinical and patient-oriented efficacy/safety outcomes of FF-VI are likely comparable to other available combinations for adults with asthma. Patient-friendly features include once-daily dosing, flexibility of dose timing, and design/ease of the use of the device. Additional larger and long-term comparative studies are needed to determine whether these features translate into greater efficacy, safety, patient preference, or adherence versus other ICS-LABA combinations. In the next few years, the availability of less expensive generic ICS-LABA products may strongly influence patient preference.


Sleep disorders in morbid obesity.
The increasing prevalence of obesity has lead to an increase in the prevalence of sleep disordered breathing in the general population. The disproportionate structural characteristics of the pharyngeal airway and the diminished neural regulation of the pharyngeal dilating muscles during sleep predispose the obese patients to pharyngeal airway collapsibility. A subgroup of obese apneic patients is unable to compensate for the added load of obesity on the respiratory system, with resultant daytime hypercapnia. Weight loss using dietary modification and life style changes is the safest approach to reducing the severity of sleep apnea, but its efficacy is limited on the long run. Although it has inherent risks, bariatric surgery provides the most immediate result in alleviating sleep apnea. Obesity has been linked also to narcolepsy. The loss of neuropeptides co-localized in hypocretin neurons is suggested as the potential mechanism. Poor sleep quality, which leads to overall sleep loss and excessive daytime sleepiness has also become a frequent complaint in this population. Identifying abnormal nocturnal eating is critically important for patient care. Both sleep related eating disorder and night eating syndrome are treatable and represent potentially reversible forms of obesity.


The number of butterfly species in woodlands.
The number of butterfly species present in 22 woods in eastern England was recorded during fortnightly visits between May to October 1978. A total of 26 species was observed. The number of species present was significantly correlated with the area of woodland but not with the area of glades and rides, which provided both larval food plants and adult foraging sites. The number of vagile species, but not the number of poorly vagile species, present was correlated with the area of woodland within 1 km of the study wood, this being a measure of the sources of potential colonizers. It was predicted that a woodland area of about 460 ha would be required to support all the species recorded in the study.


Vascular Endothelial Function in Midlife/Older Adults Classified According to 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines.
Background Impaired endothelial function is thought to contribute to the increased cardiovascular risk associated with above-normal blood pressure (BP). However, the association between endothelial function and BP classified by 2017 American College of Cardiology/American Heart Association guidelines is unknown. Our objective was to determine if endothelial function decreases in midlife/older adults across the 2017 American College of Cardiology/American Heart Association guidelines BP classifications and identify associated mechanisms of action. Methods and Results A retrospective analysis of endothelial function (brachial artery flow-mediated dilation) from 988 midlife/older adults (aged 50+ years) stratified by BP status (normal BP; elevated BP; stage 1 hypertension; stage 2 hypertension) was performed. Endothelium-independent dilation (sublingual nitroglycerin), reactive oxygen species-mediated suppression of endothelial function (∆brachial artery flow-mediated dilation with vitamin C infusion), and endothelial cell and plasma markers of oxidative stress and inflammation were assessed in subgroups. Compared with normal BP (n=411), brachial artery flow-mediated dilation was 12% (P=0.04), 15% (P<0.01) and 20% (P<0.01) lower with elevated BP (n=173), stage 1 hypertension (n=248) and stage 2 hypertension (n=156), respectively, whereas endothelium-independent dilation did not differ (P=0.14). Vitamin C infusion increased brachial artery flow-mediated dilation in those with above-normal BP (P≤0.02) but not normal BP (P=0.11). Endothelial cell p47phox (P<0.01), a marker of superoxide/reactive oxygen species-generating nicotinamide adenine dinucleotide phosphate oxidase, and circulating interleukin-6 concentrations (P=0.01) were higher in individuals with above-normal BP. Conclusions Vascular endothelial function is progressively impaired with increasing BP in otherwise healthy adults classified by 2017 American College of Cardiology/American Heart Association guidelines. Impaired endothelial function with above-normal BP is mediated by excessive reactive oxygen species signaling associated with increased endothelial expression of nicotinamide adenine dinucleotide phosphate oxidase and circulating interleukin-6.


Development, triploblastism, physics of wetting and the Cambrian explosion.
The Cambrian explosion is characterized by the sudden outburst of organized animal plans, which occurred circa 530 M years ago. Around that time, many forms of animal life appeared, including several which have since disappeared. There is no general consensus about "why" this happened, and why it had any form of suddenness. However, all organized animal plans share a common feature: they are triploblastic, i.e., composed of 3 layers of tissue, endoderm, ectoderm and mesoderm. I show here that, within simple hypotheses, the formation of the mesoderm has intrinsically a physical exponential dynamics, leading rapidly to triploblastism, and eventually, to animal formation. A novel physico-mathematical framework including epithelium-mesenchyme transition, visco-elastic constitutive equations, and conservation laws, is presented which allows one to describe gastrulation as a self-wetting phenomenon of a soft solid onto itself. This phenomenon couples differentiation and migration during gastrulation, and leads in a closed form to an exponential scaling law for the formation of the mesoderm. Therefore, the Cambrian explosion might have started, actually, by a true viscoelastic "explosion": the exponential run-away of mesenchymal cells.


Importance of beta-adrenoceptor function in fat cells for lipid mobilization.
The role of peripheral catecholamine sensitivity in lipid mobilization was investigated in 78 healthy non-obese subjects by comparing beta-adrenergic regulation of lipolysis in isolated adipocytes with circulating catecholamines and glycerol (lipolysis index). Small intra-individual variations (5-7%) in adipocyte lipolytic beta-adrenoceptor sensitivity (ED50) for isoprenaline were found. However, large inter-individual variations (almost 10(5)-fold) in isoprenaline ED50 were observed in abdominal or gluteal adipocytes, which correlated (r = 0.52) negatively with the resting plasma noradrenaline levels. A correlation was also observed between circulating noradrenaline and adipocyte ED50 for noradrenaline (r = -0.38). In subjects with high (ED50 less than 10(-11) mol l-1) as compared to low isoprenaline sensitivity (ED50 greater than 10(-10) mol l-1) physical exercise induced a two times greater increase in plasma glycerol (P less than 0.01), in spite of a 50% less marked increase of plasma noradrenaline (P less than 0.01). Findings with beta-adrenoceptor mRNA and with total beta-adrenoceptor number or affinity for agonist did not show any strong correlation with the resting plasma noradrenaline level (r less than 0.25). In conclusion, inter-individual variations in beta-adrenoceptor sensitivity and its relation to circulating noradrenaline can be ascribed to specific modulations of either BAR-subtypes or in the postreceptor activation of lipolysis. These variations in adipocyte beta-adrenoceptor sensitivity may participate in the regulation of peripheral nervous activity and play a putative role in lipolysis during exercise when subjects with high beta-adrenoceptor sensitivity increased their ability to mobilize lipids despite a reduced noradrenaline response.


Sleep-waking discharge of basal forebrain projection neurons in cats.
We have previously described a population of neurons in the magnocellular basal forebrain which have selectively elevated discharge rates during slow-wave sleep compared to waking; we postulate that these sleep-active neurons are a component of a basal forebrain sleep-promoting system. The purpose of the present experiment was to determine if sleep-active neurons contribute axons to recently described basal forebrain projection pathways. In cats prepared for chronic single unit and EEG-sleep recordings, stimulating electrodes were placed in the mesencephalic reticular formation, and the external capsule and anterior cingulate bundle, fiber bundles known to contain axons of basal forebrain projection neurons. Fifty-nine neurons were antidromically driven; differences in antidromic response latencies were related to sleep-waking discharge profiles. Of the cells with short antidromic latencies (less than 5 msec), the majority (9 of 12) had high discharge rates during waking and low rates during slow-wave sleep. Cells with long antidromic latencies had either very low discharge rates (less than 1 spike/sec) across all states, or had elevated discharge rates in slow-wave sleep. Sleep-active neurons were antidromically driven from external capsule (n = 9), anterior cingulate bundle (n = 9), or mesencephalic reticular formation (n = 5). Projection sleep-active neurons were recorded in the substantia innominata, ventral to the globus pallidus and medial to the central nucleus of the amygdala. Our study found that identified basal forebrain projection neurons in cats exhibit a variety of sleep-waking discharge patterns and conduction velocities. Sleep-active neurons were found to have slowly conducting axons, and to be a source of both ascending and descending projections.


Synthesis of organo-silane functionalized nanocrystal micelles and their self-assembly.
We report a general method to synthesize gold nanocrystal micelles with organo-silane headgroups. The method involves encapsulation of monodisperse, hydrophobic gold nanocrystals within the core of a micelle of an amphiphilic silane precursor. Formation and stability of monodisperse gold NC micelles have been confirmed using UV-visible spectroscopy and transmission electron microscopy. Self-assembly of such nanocrystal micelles through siloxane hydrolysis and cross-linking leads to an ordered array with a face-centered-cubic mesostructure.


Incidence and clinical outcomes of pneumonia in persons with down syndrome in the United States.
Persons with Down syndrome (DS) experience an increased risk of pneumonia. We determined the incidence and outcomes of pneumonia and relationship to underlying comorbidities in persons with and without DS in the United States. This retrospective matched cohort study used de-identified administrative claims data from Optum. Persons with DS were matched 1:4 to persons without DS on age, sex, and race/ethnicity. Pneumonia episodes were analyzed for incidence, rate ratios and 95 % confidence intervals, clinical outcomes, and comorbidities. During 1-year follow-up among 33796 persons with and 135184 without DS, the incidence of all-cause pneumonia (pneumonia) was substantially higher among people with DS than those without DS (12427 vs. 2531 episodes/100000 person-years; 4.7-5.7 fold increase). Persons with DS and pneumonia were more likely to be hospitalized (39.4 % vs. 13.9 %) or admitted to the ICU (16.8 % vs. 4.8 %). Mortality was higher 1 year after first pneumonia (5.7 % vs. 2.4 %; P < 0.0001). Results were similar for episodes of pneumococcal pneumonia. Specific comorbidities were associated with pneumonia, particularly heart disease in children and neurologic disease in adults, which only partially mediated the effect of DS on pneumonia. Among persons with DS, incidence of pneumonia and associated hospitalizations were increased; mortality among those with pneumonia was comparable at 30 days, but higher at 1 year. DS should be considered an independent risk condition for pneumonia.


Mediastinal parathyroid cyst. Report of a case and review of the literature.
A case of mediastinal parathyroid cyst is presented, including a review of the world literature and a discussion of the etiology, diagnosis, and management.


The calibration of thermocouples for leaf temperature measurements in gas exchange cuvettes.
A thermocouple shows a high accuracy in reading temperatures, but it does not always give a true value for the temperature of the leaf against which it is pressed on. Temperature differences between the leaf and the air moving around it cause deviations of the shown temperature from the actual leaf temperature. A method is described to calibrate thermocouples inside gas exchange cuvettes without obstructing the movement of the air around the leaf, so that the heat exchange between thermocouple and air is taken into account. The reading of the leaf temperature in a steady-state porometer was checked by this method at various temperatures of ambient air (T a ) and of the leaf (T 1 ) and was found to give an average value of T a and T 1 . The effect of incorrect estimation of the leaf temperature on computed diffusive resistances on H2O (r w ) and CO2 (r c ) and intercellular CO2 partial pressures (p ic ) is discussed.


Chromatofocusing fractionation and two-dimensional difference gel electrophoresis for low abundance serum proteins.
The technical challenge to analysis of the serum proteome is that the serum proteins are present at unequal concentrations. A few are so dominant, such as serum albumin and immunoglobulins, that they mask detection of other proteins. Because of these high abundance proteins, current technologies, while theoretically capable of analyzing protein amounts spanning four orders of magnitude, are only able to analyze proteins ranging over two orders of magnitude and cannot analyze the lower abundance proteins that may be the next biomarkers and drug targets. To facilitate the identification of low abundance proteins, we fractionated serum samples from patients with prostate cancer and patients with benign prostate hyperplasia using anion displacement liquid chromatofocusing chromatography, which separates proteins by a pH gradient and a positively charged column. Differential expression of proteins from fractions was then determined and identified by IEF gels and 2-D DIGE. Results demonstrate improved resolution of proteins within the chosen pH gradient when compared to the unfractionated samples. Several proteins that were differentially expressed in serum from patients with prostate cancer were identified in the fractionated serum. Three of these proteins, squamous cell carcinoma antigen 1 (SCCA1), calgranulin B, and haptoglobin-related protein, are present in the serum at levels below the classical protein level of mg/mL. SCCA1 is normally expressed in serum at ng/mL levels, and calgranulin B is an intracellular protein. Our results demonstrate that the use of anion displacement liquid chromatofocusing chromatography may reduce the complexity of the serum proteome by separating proteins into distinct pH ranges, and facilitate the identification of low abundance proteins.


Molecular bases of cellular iron toxicity.
Patients with hereditary or secondary hemochromatosis are liable to cardiac and hepatic failure, and type II diabetes. Despite the highly likely conjecture that iron-mediated tissue damage involves the conspiracy of cellular oxidizing and reducing equivalents, the pathophysiologic events have not been fully elucidated. These latter likely involve toxic effects of iron on intracellular organelles, in particular, mitochondria and lysosomes. The tissues at risk-heart, liver, and pancreatic beta cells-all have highly active mitochondria, which incidentally generate activated oxygen species capable of causing synergistic toxicity with intracellular iron. This suggests the general concept that iron may be preferentially toxic to cells with high mitochondrial activity. At least part of the long-term toxicity may involve iron-mediated oxidative damage to the mitochondrial genome with an accumulation of mutational events leading to progressive mitochondrial dysfunction. An alternative-and not mutually exclusive-mechanism for cellular iron toxicity involves iron-catalyzed oxidative destabilization of lysosomes, leading to leak of digestive enzymes into the cell cytoplasm and eventuating in apoptotic or necrotic cell death.


[Endoscopy in the diagnosis and therapy of surgical diseases. Colonoscopic diagnosis (author's transl)].
Fibroscopes and the techniques of introducing them are now so highly developed that, except for an impassable stenosis, the entire colon can be inspected in every case and the adjacent small intestine in 90% of the cases. Indisputable advantages as compared with indirect methods such as radiology are the direct inspection of the mucosa, the possibility of reliably differentiating between pathological findings and residual stool, the detection of minute lesions that escape radiological examination, and the possibility of removing tissue samples (forceps biopsy, big-particle biopsy, polypectomy). Thus it is possible for the first time to confirm diagnosis morphologically prior to surgery.


Exercise testing using upper extremity ergometry in pediatric spinal cord injury.
To describe an upper extremity ergometer test for children with spinal cord injury (SCI) and examine differences based on injury level for peak heart rate (HR peak), oxygen uptake (VO 2 peak/kg), and peak power output per kilogram (W peak/kg). Twenty-nine children with motor complete SCI participated. Nine had low cervical (C7, C8), 9 had upper thoracic (T1-T4), and 11 had mid/low thoracic (T5-T11) SCI. HR peak, VO2 peak/kg, and W peak/kg were compared based on these 3 injury level groupings. HR peak (p = 0.013), VO 2 peak/kg (p = 0.041), and W peak/kg (p = 0.001) differed between groups. The mid/low thoracic group had the highest values for each variable. The differences in HR peak, VO 2 peak/kg, and W peak/kg were consistent with exercise effects reported for adults with SCI. Further research is needed to develop an appropriate standardized ergometric test for children with SCI.


Posttraumatic stress disorder and substance abuse. Clinical issues.
A review of clinical issues relevant to the treatment of individuals with a combination of posttraumatic stress disorder and substance abuse disorder is presented. There are several issues that these two disorders share, including the need for heightened awareness on the part of clinicians, the ability to make the diagnoses, the conceptualization of etiological factors, and the issues of therapeutic attitudes and countertransference problems. In addition, a brief review of relevant therapeutic approaches is presented and treatment priorities discussed.


From here to Utopia: Theories of Change in Nonideal Animal Ethics.
Animal ethics has often been criticized for an overreliance on "ideal" or even "utopian" theorizing. In this article, I recognize this problem, but argue that the "nonideal theory" which critics have offered in response is still insufficient to make animal ethics action-guiding. I argue that in order for animal ethics to be action-guiding, it must consider agent-centered theories of change detailing how an ideally just human-animal coexistence can and should be brought about. I lay out desiderata that such a theory of change should suffice so as to be helpful in guiding action. Specifically, a theory of change should determine (1) who needs to do what in order for ideal justice to be achieved in the long run, (2) who should be expected to refuse compliance and how they should be moved to comply, and (3) why specific intermediate steps are necessary. I show how previous "nonideal" contributions, though helpful in other ways, are insufficiently determinate on these points and I sketch a (still somewhat utopian) theory of change for one specific context. This brings animal ethics a crucial step closer to being action-guiding in the real world.


Laboratory diagnosis of toxoplasmosis.
Acute infection with Toxoplasma gondii is diagnosed by (i) detection of the parasite directly in patients' specimens using histological or immunological methods, (ii) isolation of T. gondii from blood, body fluids or tissue by inoculation in laboratory mice or on tissue culture cells, or (iii) serological methods for determination of a significant, T. gondii-specific, antibody titre rise or of T. gondii specific IgM (or IgA) antibody. Because of their high sensitivity, specificity and relative ease of performance, serological methods are preferentially used for diagnosis of T. gondii infection. The diagnosis of acute, postnatally-acquired, primary toxoplasmosis is usually established by serological methods and will in general present few problems. However, diagnosis of congenital infections and their late sequelae or of reactivation of a latent infection in immunocompromised patients is often more troublesome because of the absence of a significant antibody titre rise or the lack of specific IgM antibody. In these cases a combination of various methods may be required for definitive diagnosis of T. gondii infection.


Repeated triplets complicated by monochorionic diamniotic twins following assisted reproduction: a case report and literature review.
Monochorionic twinning involves numerous maternal and fetal complications, triplets complicated by a monochorionic pair are at further increased risk. Here, we report a case of repeated triplets complicated by monochorionic diamniotic twins with successful pregnancy outcomes in a woman using autologous oocytes. A 30-year-old female undergoing embryo transfer with fresh and frozen embryo cycles with autologous oocytes. The two cycles were confirmed by transvaginal ultrasound to result in successful clinical pregnancies of triplets complicated by a monochorionic twinning. The first pregnancy resulted in a singleton delivery after a selective reduction of the monochorionic pair. The subsequent pregnancy resulted in a dichorionic diamniotic twin pregnancy after the heartbeat of one of the monochorionic twin fetuses stopped at 43 days after embryo transfer. Both of the pregnancies ended with successful live births. Our case report of repeated triplets with monochorionic twins suggests the potential causes and risk factors of monochorionic twinning in assisted reproduction and raises concern regarding the timing of multifetal pregnancy reduction.


Experimental studies on the role of alkyl lysophospholipids in autologous bone marrow transplantation.
The selective cytocidal effect of alkyl lysophospholipids against neoplastic cells while sparing normal cells make these ideal candidates for purging leukemic cells from bone marrows obtained during remission. To test the feasibility of such an approach, a murine model and an in vitro human cell model were developed. In the murine system a mixture of normal bone marrow cells and WEHI IIIB myelomonocytic leukemic cells was incubated with varying doses of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-Me) for 24 hr before being injected into tail veins of lethally irradiated Balb/c mice. At doses of 20 and 100 micrograms/ml, long-term survivors were noted. The additional steps of freezing and thawing following incubation resulted in significantly longer survival with doses of 10 to 50 micrograms/ml, but were toxic to marrow stem cells at 100 micrograms/ml. In the in vitro model, normal marrow progenitor cells and leukemic cells (the promyelocytic cell line HL60) were exposed to varying concentrations of ET-Me for 1 and 4 hr alone or mixed, and clonogenicity was assayed by colony formation in semisolid medium during 7-14 days' incubation. At doses up to 100 micrograms/ml exposed for 4 hr normal progenitor cells were spared and HL60 colonies eliminated. Other phospholipids analogues were less effective in eliminating leukemic cells, but spared normal progenitor cells. A survey of fresh leukemic cells found varying degrees of sensitivity to ET-Me, indicating the need for testing a variety of compounds. These studies clearly indicated the potential usefulness of alkyl lysophospholipid compounds in selectively purging leukemic cells from remission marrows for autologous bone marrow transplantation.


Undesirable odour substances (geosmin and 2-methylisoborneol) in water environment: Sources, impacts and removal strategies.
Off-flavours in fish products generated from recirculating aquaculture systems (RAS) are a major problem in the fish farming industry affecting the market demand and prices. A particular concern is the muddy or musty odour and taste in fish due to the presence of secondary metabolites geosmin and 2-methylisoborneol (2-MIB), produced by actinobacteria (mainly Streptomyces), myxobacteria and cyanobacteria. Off-flavours have deteriorated the quality of fish, rendering their products unfit for human consumption. The process of odour removal requires purification for several days to weeks in clean water; thus this leads to additional production costs. Geosmin and 2-MIB, detected at extremely low odour thresholds, are the most widespread off-flavour metabolites in aquaculture, entering through fish gills and accumulating in the fish adipose tissues. In this review, we aimed to determine the diversity and identity of geosmin- and 2-MIB-producing bacteria in aquaculture and provide possible strategies for their elimination.


Temporal trends in "legacy" organochlorine contaminants in blubber of ringed seals (Phoca hispida) from Ulukhaktok, NT, Canada between 1972 and 2010.
In blubber of ringed seals (Phoca hispida) from Ulukhaktok, NT, residues of DDT, other organochlorine pesticides, and PCBs declined between 1972 and 2010. The rate of decline varied: concentrations of the DDT-group began to fall after 1981, whereas those of PCBs fell rapidly between 1972 and 1981, and then slowed. Concentrations of cis- and trans-chlordane and of HCB in both sexes, and of cis-nonachlor in males, declined slowly between 1978 and 2010; those of other organochlorine pesticides remained steady. Exponential half-lives of p,p'-DDT and p,p'-DDE in female seals are about 9 and 36 y (corresponding to initial declines of 7.8% and 1.9% per year, respectively) and those of PCB congeners from about 20 to 60 y (declines of 3.2% to <1.5% per year); the more refractory residues may be detectable for centuries to come. Exploratory PCA of PCB congener distribution identified temporal changes apparently not related to molecular structure.


The interaction between BMI, weight criticism, weight bias, and psychological and relational outcomes within marriage.
To examine (1) whether a wife's BMI interacts with either her husband's weight stigma or (2) her perceived weight criticisms from her husband predict husbands' and wives' psychological and relational outcomes. The study sample consisted of 209 currently married men and women in a heterosexual relationship. Participants were drawn from an online survey platform (Qualtrics, Inc. Provo, UT) designed to approximate the US population on age, race, and region of the country. Online measures assessed husbands' weight stigma, wives' perceived weight criticisms from husband, and husbands' and wives': (1) relationship satisfaction, (2) sexual intimacy, (3) self-esteem, (4) depressive symptoms, and (5) perceptions of a desirable or ideal mate. Wives' BMI interacted with husbands' weight stigma to predict (1) mate value for husbands and wives and (2) marital satisfaction for husbands. The same pattern was noted with interaction of wives' BMI and perceptions of husbands' weight related criticisms. The interaction reflected that higher wife BMI and higher husband weight stigma or wife perceived weight-related criticism predicted lower marital satisfaction, greater depression, and lower perceptions of a desirable or an ideal mate. Lower BMI was not associated with outcomes regardless of the husbands' weight stigma or wives' perceived weight-related criticisms. To understand the impact of weight stigma and weight related criticisms on perceptions of a desirable or ideal mate and marital outcomes, it is important to examine the interaction with partner's BMI. III: Evidence obtained from cohort or case-control analytic studies.


A controlled trial of percutaneous adrenal arterial embolization for hypertension in patients with idiopathic hyperaldosteronism.
Our prior study has suggested that percutaneous superselective adrenal arterial embolization (SAAE) with ethanol reduces blood pressure in patients with primary aldosteronism. This study aimed to compare the efficacy of SAAE with mineralocorticoid receptor antagonists (MRA) in treating patients with idiopathic hyperaldosteronism. In this prospective, randomized, controlled trial, we randomly assigned patients with idiopathic hyperaldosteronism in a 1:1 ratio to undergo SAAE (n = 29) or receive MRA (n = 30) treatment. The primary endpoint was the change in mean 24-hour ambulatory systolic blood pressure at 6 months. The secondary endpoints included changes in office blood pressure, home blood pressure, correction of aldosterone-to-renin ratio, and adverse events at 6 months. The mean change in 24-h ambulatory systolic blood pressure from baseline to 6-month follow-up was significantly different between the two groups (-8.4 mmHg; 95% confidence interval, -15.2 to -2.1 mmHg; P < 0.01). Office, home, and ambulatory blood pressure reduction at 6 months was more pronounced in the SAAE group than the MRA group (all P < 0.05). Aldosterone-to-renin ratio was lower in the SAAE group than the MRA group at 1 and 3 months (both P < 0.01), while it had no difference between the two groups at 6 months. None of the patients experienced serious adverse events in the perioperative and 6-month follow-up periods. SAAE, as a hormonal debulking procedure, is superior to MRA in blood pressure control and correction of biochemical abnormalities in patients with idiopathic hyperaldosteronism.


A case of co-existing pigmented villonodular synovitis and tuberculosis infection of the foot and ankle.
A woman presented with chronic left ankle pain and swelling with no systemic upset. Magnetic resonance imaging suggested pigmented villonodular synovitis (PVNS) of her left ankle joint and flexor hallucis longus tendon. Combined arthroscopic and open synovectomy was performed. Histological examination of the synovium confirmed the diagnosis of PVNS, but culture of the diseased synovium yielded mycobacterium tuberculosis. This case illustrates the possibility of double pathology and the importance in excluding tuberculosis infection.


Activation of bone marrow-resident memory T cells by circulating, antigen-bearing dendritic cells.
Dendritic cells (DCs) carry antigen from peripheral tissues via lymphatics to lymph nodes. We report here that differentiated DCs can also travel from the periphery into the blood. Circulating DCs migrated to the spleen, liver and lung but not lymph nodes. They also homed to the bone marrow, where they were retained better than in most other tissues. Homing of DCs to the bone marrow depended on constitutively expressed vascular cell adhesion molecule 1 and endothelial selectins in bone marrow microvessels. Two-photon intravital microscopy in bone marrow cavities showed that DCs formed stable antigen-dependent contacts with bone marrow-resident central memory T cells. Moreover, using this previously unknown migratory pathway, antigen-pulsed DCs were able to trigger central memory T cell-mediated recall responses in the bone marrow.


Immunoinformatic and reverse vaccinology-based designing of potent multi-epitope vaccine against Marburgvirus targeting the glycoprotein.
Marburg virus (MARV) has been a major concern since its first outbreak in 1967. Although the deadly BSL-4 pathogen has been reported in few individuals with sporadic outbreaks following 1967, its rarity commensurate the degree of disease severity. The virus has been known to cause extreme hemorrhagic fever presenting flu-like symptoms (as implicated in COVID-19) with a 90% case fatality rate (CFR). After a number of plausible evidences, it has been observed that the virus usually originates from African fruit bat, Rousettus aegyptiacus, who themselves do not indicate any signs of illness. Thus, efforts have been made in the recent years for a universal treatment of the infection, but till date, no such vaccine or therapeutics could circumvent the viral pathogenicity. In an attempt to formulate a vaccine design computationally, we have explored the entire proteome of the virus and found a strong correlation of its glycoprotein (GP) in receptor binding and subsequent role in infection progression. The present study, explores the MARV glycoprotein GP1 and GP2 domains for quality epitopes to elicit an extended immune response design potential vaccine construct using appropriate linkers and adjuvants. Finally, the chimeric vaccine wass evaluated for its binding affinity towards the receptors via molecular docking and molecular dynamics simulation studies. The rare, yet deadly zoonotic infection with mild outbreaks in recent years has flustered an alarming future with various challenges in terms of viral diseases. Thus, our study has aimed to provide novel insights to design potential vaccines by using the predictive framework.


Effect of KC-9432, a new hypolipidemic compound, on high density lipoprotein cholesterol in rats.
KC-9432 (a new hypolipidemic compound, alpha-[p-(p-chlorobenzoyl) phenoxy-alpha-cyclohexyl acetic acid ethyl ester) was studied in rats for its effect on plasma lipid and lipoprotein levels. KC-9432 was particularly effective in hyperlipidemia in rats fed with a diet containing 2% cholesterol and 1% sodium cholate. The hypocholesterolemic activity of KC-9432 was far more potent than that of clofibrate. KC-9432 markedly increased the reduced HDL cholesterol level in dietary-induced hyperlipidemia in rats.


Effect of deoxycytidine on the in vitro response of human leukemia cells to inhibitors of de novo pyrimidine biosynthesis.
The effect of high concentrations of exogenous dCyd on the growth inhibitory properties of several inhibitors of de novo pyrimidine biosynthesis (dThd, 3-DAU, PALA, PF) was examined in three cultured human leukemic cell lines (HL-60, K-562, KG-1), and a dCyd kinase-deficient, Ara-C-resistant variant (HL-60/Ara-C). In the presence of dCyd concentrations (10(-3) M), far exceeding normal human plasma levels (0.5 to 4.0 X 10(6) M), substantial but partial reversal of pyrimidine antagonist-mediated growth inhibition and restoration of intracellular dCTP levels was noted in all cell types except HL-60/Ara-C. When high concentrations of dCyd (10(-3) M) were combined with low levels of uridine or cytidine (10(-5) M), full restoration of growth was observed in sensitive cell lines. When exposed to supraphysiologic concentrations of dCyd, HL-60/Ara-C cells were more sensitive to the growth inhibitory effects of pyrimidine antagonists than parent HL-60 cells; this phenomenon was maximal at 10(-4) M dCyd and was not observed in the presence of dCyd concentrations of 10(-6) M or lower. These studies suggest that in the presence of low concentrations of uridine or cytidine, perturbations in intracellular dCTP pools may play a critical role in determining the in vitro antiproliferative response of human leukemic myeloid cells to diverse inhibitors of de novo pyrimidine biosynthesis. They also raise the possibility that modulation of exogenous dCyd concentrations may improve the therapeutic efficacy of pyrimidine antagonists toward certain salvage pathway-deficient, drug-resistant leukemic cells.


Growth hormone and prolactin responses to corticotrophin-releasing-hormone in patients with Cushing's disease: a paracrine action of the adenomatous corticotrophic cells?
In patients with Cushing's disease multihormonal responses to ovine corticotrophin releasing hormone (oCRH) have been detected in blood from inferior petrosal sinuses. This finding has been explained by co-secretion of other hormones, in addition to ACTH, by the pituitary adenoma itself or by paracrine effects exerted by the adenoma on normal periadenomatous pituitary cells. To assess these hypotheses we compared the presence of a CRH induced GH and/or PRL response during inferior petrosal sinus sampling to the immunohistochemical detection of PRL and GH in adenomatous tissue removed from patients with Cushing's disease. Twenty-two patients with Cushing's disease and two patients with ectopic ACTH syndrome due to a bronchial carcinoid were studied; each patient had undergone preoperative inferior petrosal sinus sampling for diagnostic purposes with determination of GH and PRL in addition to ACTH, before and after administration of oCRH. Immunohistochemical studies for ACTH, GH and PRL detection were carried out on adenomatous tissue removed at surgery in the patients with pituitary dependent Cushing's disease and on the carcinoid tumours from the two patients with ectopic ACTH syndrome. All pituitary adenomas immunostained for ACTH, and four adenomas immunostained for GH or PRL in addition to ACTH. A PRL increase in the inferior petrosal sinus after oCRH administration was found in 11 of 22 patients, but none of their tumours immunostained for PRL. Immunostaining for PRL was found in the pituitary tumours from two patients but in neither patient was there a PRL response after oCRH. A GH response was found in 13 of 20 patients in whom it was sought; no patient showed immunostaining in their tumour. GH immunostaining was found in two tumours but in neither patient was there a GH response after oCRH. The oCRH-induced increase of GH and PRL was always recorded in the dominant inferior petrosal sinus. The ACTH response to oCRH was significantly higher in patients who showed oCRH induced increases in GH and/or PRL than in patients who did not, both in terms of area under the response-curve (22,032 +/- 9876 vs. 4371 +/- 2870 ng/l/10 min; P < 0.05) or mean percentage increase above baseline (754 +/- 229% vs. 147.2 +/- 67%, P < 0.02). A significant correlation was observed between ACTH and GH responses to oCRH. The two patients with ectopic Cushing's syndrome did not show ACTH, GH or PRL increases after oCRH administration and did not show immunostaining for GH or PRL in their tumours. The present data do not support the hypothesis of co-secretion of hormones by the pituitary adenoma as the cause of the GH and PRL responses to ovine corticotrophin releasing hormone observed in patients with Cushing's disease; it is suggested that a different mechanism, possibly involving an interaction between the ACTH secreting adenoma and the normal periadenomatous GH and PRL secreting cells, may be responsible.


Cutaneous tuberculosis: a clinical, histopathologic, and bacteriologic study.
In recent years cutaneous infections with Mycobacterium tuberculosis with an atypical clinical appearance have become more common because of the increasing number of immunocompromised patients. We report the clinical, histopathologic, and bacteriologic data of 11 patients with several forms of cutaneous tuberculosis seen during the past 14 years. Patients from whom M. tuberculosis was isolated from culture of skin biopsy specimens, sinus drainage, or material aspirated from cutaneous abscesses were included. In all but two patients a biopsy specimen was obtained for histopathologic study. All but one patient received combined antituberculous therapy. The clinical diagnoses were scrofuloderma (four cases), cutaneous miliary tuberculosis (two), lupus vulgaris (two), tuberculous gumma (two), and one unclassified. All but three patients had evidence of either previous or simultaneous tuberculous foci other than in the skin. Histopathologic findings varied according to the type of cutaneous tuberculosis. In some patients with cutaneous tuberculosis, lesions are atypical in appearance because of immunodeficiency. Culture for M. tuberculosis should be performed in all suspected cases, even in those in whom special stains for acid-fast bacilli are negative.


Heat shock protein90 in lobular neoplasia of the breast.
Heat shock protein 90 (Hsp90) overexpression has been implicated in breast carcinogenesis, with putative prognostic and therapeutic implications. The purpose of this study is to evaluate the immunohistochemical expression of Hsp90 and to examine whether Hsp90 expression is associated with estrogen receptor alpha (ER-alpha) and beta (ER-beta) immunostaining in lobular neoplasia (LN) of the breast. Tissue specimens were taken from 44 patients with LN. Immunohistochemical assessment of Hsp90, ER-alpha and ER-beta was performed both in the lesion and the adjacent normal breast ducts and lobules; the latter serving as control. As far as Hsp90 evaluation is concerned: i) the percentage of positive cells, and ii) the intensity was separately analyzed. Additionally, the Allred score was adopted and calculated. Accordingly, Allred score was separately evaluated for ER-alpha and ER-beta. The intensity was treated as an ordinal variable-score (0: negative, low: 1, moderate: 2, high: 3). Statistical analysis followed. Hsp90 immunoreactivity was mainly cytoplasmic in both the epithelial cells of normal breast (ducts and lobules) and LN. Some epithelial cells of LN also showed nuclear staining, but all the LN foci mainly disclosed a positive cytoplasmic immunoreaction for Hsp90. In addition, rare intralobular inflammatory cells showed a slight immunoreaction. The percentage of Hsp90 positive cells in the LN areas was equal to 67.1 +/- 12.2%, whereas the respective percentage in the normal adjacent breast tissue was 69.1 +/- 11.6%; the difference was not statistically significant. The intensity score of Hsp90 staining was 1.82 +/- 0.72 in LN foci, while in the normal adjacent tissue the intensity score was 2.14 +/- 0.64. This difference was statistically significant (p = 0.029, Wilcoxon matched-pairs signed-ranks test). The Hsp90 Allred score was 6.46 +/- 1.14 in the LN foci, significantly lower than in the normal adjacent tissue (6.91 +/- 0.92, p = 0.049, Wilcoxon matched-pairs signed-ranks test). Within the LN foci, the Hsp90 Allred score was neither associated with ER-alpha, nor with ER-beta percentage. Hsp90 was lower in LN foci both at the level of intensity and Allred score, a finding contrary to what might have been expected, given that high Hsp90 expression is detected in invasive breast carcinomas. Hsp90 deregulation does not seem to be a major event in LN pathogenesis.


The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia.
With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (https://sarcoatlas.scicore.unibas.ch/), as a user-friendly gene discovery tool. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging.


A method for molecular phylogeny construction by direct use of nucleotide sequence data.
A method for molecular phylogeny construction is newly developed. The method, called the stepwise ancestral sequence method, estimates molecular phylogenetic trees and ancestral sequences simultaneously on the basis of parsimony and sequence homology. For simplicity the emphasis is placed more on parsimony than on sequence homology in the present study, though both are certainly important. Because parsimony alone will sometimes generate plural candidate trees, the method retains not one but five candidates from which one can then single out the final tree taking other criteria into account. The properties and performance of the method are then examined by simulating an evolving gene along a model phylogenetic tree. The estimated trees are found to lie in a narrow range of the parsimony criteria used in the present study. Thus, other criteria such as biological evidence and likelihood are necessary to single out the correct tree among them, with biological evidence taking precedence over any other criterion. The computer simulation also reveals that the method satisfactorily estimates both tree topology and ancestral sequences, at least for the evolutionary model used in the present study.


Microparticles derived from endothelial progenitor cells in patients at different cardiovascular risk.
Exposure to cardiovascular risk factors causes the release of pro-atherogenic microparticles from vascular cells and reduces the number of the atheroprotective endothelial progenitor cells (EPCs). We investigated whether microparticles shedding from EPCs are detectable in cultures of EPCs and in the circulation of subjects with various degrees of cardiovascular risk. We also investigated the relationship of EPCs-derived microparticles to cardiovascular risk factors and aortic stiffness, a marker of cardiovascular risk and impaired vascular repair by EPCs. We estimated the 10-year Framingham risk score in 105 individuals with various degrees of cardiovascular risk and measured the number of circulating EPCs, EPCs-derived microparticles (CD34+/KDR+) and aortic stiffness. Release of CD34+/KDR+ microparticles was tested in cultures of EPCs exposed to hydrogen-peroxide. CD34+/KDR+ microparticles were found in EPCs cultures incubated with hydrogen-peroxide. Framingham risk was associated with EPCs (r=-0.47, p<0.001) and CD34+/KDR+ microparticles (r=0.56, p<0.001). Low EPCs (r=-0.59, p<0.001) and high CD34+/KDR+ microparticle (r=0.57, p<0.001) levels were predictors of aortic stiffness, independent of the Framingham risk. EPCs undergo fragmentation into microparticles when exposed to a pro-apoptotic milieu. Increased microparticle shedding from EPCs may reduce circulating EPCs levels and may thus contribute to increase aortic stiffness beside traditional risk factors.


Objective food environments and health outcomes.
Pathways by which food environments affect residents' diet-related outcomes are still unclear. Understanding pathways may help decision makers identify food environment strategies to promote healthy diets. To examine the hypothesis that residents' perceptions mediate the relationship between objective food environment and residents' diet quality and weight status. In the Waterloo Region, Ontario, objective food environment data were collected from 422 food stores and 912 restaurants using the Nutrition Environment Measure Survey in Stores and Restaurants, a shelf-space measure of fruits and vegetables, and the Retail Food Environment Index. Waterloo Region households (n=2223) completed a subjective food environment perception survey; household members (n=4102) self-reported weight, height, and waist circumference. A subsample (1170 individuals within 690 households) completed diet records. Food environment data were collected in 2010; respondent data were collected from 2009-2010; and data were analyzed in 2012. A series of gender-specific models were conducted to test mediation, adjusting for household income, car ownership, age, and education level. Residents' perceptions did not mediate the relationship between objective measures and diet-related outcomes; instead, results revealed the direct effect of several objectively measured factors of the food environment (notably food access and relative food affordability) on outcomes. Perceptions generally were not associated with diet-related outcomes. These results reveal that in this setting, strategies aimed at improving residents' perceptions may be less effective than those acting directly on food environments to improve food access and relative food affordability.


Experimental videothoracoscopic cannulation of the left atrial appendix. A feasible rapid approach for initiating left heart bypass?
Rapid implementation of left ventricular assistance without thoracotomy for temporary support of patients with severe, life-threatening, acute cardiac power failure potentially expands applications of such support devices. A thoracoscopic technique for direct cannulation of the left atrium is described. In healthy closed-chest pigs, it proved a feasible method for effective volume unloading of the left ventricle.


Invited Review Article: Instrumentation for nuclear magnetic resonance in zero and ultralow magnetic field.
We review experimental techniques in our laboratory for nuclear magnetic resonance (NMR) in zero and ultralow magnetic field (below 0.1 μT) where detection is based on a low-cost, non-cryogenic, spin-exchange relaxation free 87Rb atomic magnetometer. The typical sensitivity is 20-30 fT/Hz1/2 for signal frequencies below 1 kHz and NMR linewidths range from Hz all the way down to tens of mHz. These features enable precision measurements of chemically informative nuclear spin-spin couplings as well as nuclear spin precession in ultralow magnetic fields.


Passivation and Interlayer Effect of Zr(i-PrO)4 on Green CuGaS2/ZnS/Zr(i-PrO)4@Al2O3 and Red CuInS2/ZnS/Zr(i-PrO)4@Al2O3 QD Hybrid Powders.
Broadband emissive I-III-VI quantum dots (QDs) are synthesized as efficient and stable I-III-VI QDs to be used as eco-friendly luminescent materials in various applications. Here, we introduce the additional passivation of zirconium isopropoxide (Zr(i-PrO)4) to improve the optical properties and environmental stability of green-emitting CuGaS2/ZnS (G-CGS/ZnS) and red-emitting CuInS2/ZnS (R-CIS/ZnS) QDs. The photoluminescence quantum yield (PLQY) of both resultant Zr(i-PrO)4-coated G-CGS/ZnS and R-CIS/ZnS QDs reaches similar values of ~ 95%. In addition, the photostability and thermal-stability of G-CGS/ZnS/Zr(i-PrO)4 and R-CIS/ZnS/Zr(i-PrO)4 QDs are improved by reducing the ligand loss via encapsulation of the ligand-coated QD surface with Zr(i-PrO)4. It is also proved that the Zr(i-PrO)4-passivated interlayer mitigates the further degradation of I-III-V QDs from ligand loss even under harsh conditions during additional hydrolysis reaction of aluminum tri-sec-butoxide (Al(sec-BuO)3), forming easy-to-handle G-CGS/ZnS and R-CIS/ZnS QD-embedded Al2O3 powders. Therefore, the introduction of a Zr(i-PrO)4 complex layer potentially provides a strong interlayer to mitigate degradation of I-III-VI QD-embedded Al2O3 hybrid powders as well as passivation layer for protecting I-III-VI QD.