Frequency and magnitude of seroreactivity to Babesia microti in 245 patients diagnosed by PCR in New York State.
Multiple methodologies have been used to detect antibodies to Babesia microti. Use of an indirect immunofluorescence assay (IFA) has been the most widely used approach, but IFAs have varied as to which antibody class or classes are being detected and in regard to cutoff titers. In this study, 245 different patients with polymerase chain reaction (PCR)-confirmed B. microti infection were tested by a polyvalent IFA using serum collected within 3 days of the date the blood sample for PCR testing was obtained. Of the 245 patients, 243 (99.2%) had a positive serologic test result (i.e., ≥1:64). Of the 243 patients who were seropositive, 242 (99.6%) had a titer of ≥1:256, 236 (97.1%) had a titer of ≥1:512, and 210 (86.4%) had a titer of ≥1:1024. In conclusion, high titer seropositivity based on a polyvalent IFA is to be expected at the time of PCR confirmation of active babesiosis in clinical practice.


Expression of Forkhead-box protein A1, a marker of luminal A type breast cancer, parallels low Oncotype DX 21-gene recurrence scores.
The Oncotype DX assay is one of the molecular tests that provide predictive and prognostic information to breast cancer patients with estrogen receptor (ER)-positive and node-negative disease. This study evaluates the association of Forkhead-box protein A1 (FOXA1) and GATA-binding protein 3 (GATA3) expressions with Oncotype DX recurrences scores in 77 cases of patients with ER-positive node-negative breast carcinomas diagnosed at Indiana University. The data were correlated with patient age, tumor size, histologic type, Scarff-Bloom-Richardson score, histologic grade, and progesterone receptor status. The median FOXA1 and GATA3 scores were 240 and 200, respectively. The Oncotype DX recurrence scores were low in 57%, intermediate in 30%, and high in 13% of cases. FOXA1 expression correlated negatively with Oncotype DX recurrence scores (P=0.004), and histologic type (P=0.0004). Oncotype DX recurrences score also correlated negatively with progesterone receptor (P=0.035) with 100% of progesterone receptor-negative cases having high or intermediate Oncotype DX scores. FOXA1 and GATA3 expressions correlated positively (P=0.014). The correlation between FOXA1 expression and Oncotype DX recurrence scores remained significant after adjusting for multiple comparisons and controlling for confounders such as histological type, grade, and progesterone receptor. A statistically significant correlation between the Oncotype DX recurrence scores and FOXA1 expression in our diverse cohort of ER-positive breast cancer patients was observed. We propose that this may represent a more cost-effective strategy to further risk stratify patients with good prognosis in whom chemotherapy may be omitted. To confirm these findings, further studies in a larger cohort of patients are warranted.


Attentional enhancements and deficits in deaf populations: an integrative review.
The literature on visual attention in deaf individuals presents two competing views. On one hand, the deficit view proposes that auditory input is necessary for the development of visual attention; on the other hand, the compensation view holds that visual attention reorganizes to allow the individual to compensate for the lack of auditory input. While apparently contradictory, we suggest that these views shed complementary light on the cross-modal reorganization of visual attention after early deafness. First, these two fields of inquiry look at different aspects of attention. The deficit view is mostly supported by studies of allocation of attention in time, whereas the compensation view is backed by studies measuring the allocation of attention across space. Second, they focus on groups of different age and different background. Deficits have been documented mostly in children with mixed hearing loss aetiologies, whereas reorganization has been documented in a less representative, but more homogenous group of Deaf adults. We propose a more integrative view in which early auditory deprivation does not result in better or worse visual attention. Rather, selected aspects of visual attention are modified in various ways along the developmental trajectory as a result of early deafness.


Low dose chemotherapy of metastatic breast cancer with cyclophosphamide, adriamycin, methotrexate, 5-fluorouracil (CAMF) versus sequential cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and adriamycin.
Seventy-eight advanced breast cancer patients with hormone-resistant disease or visceral metastases were randomized to receive either of two low dose regimens consisting of cyclophosphamide (C), methotrexate (M), 5-fluorouracil (F), and Adriamycin (A) as their initial chemotherapy. One group was treated with CAMF, and the other with CMF until progression, followed by A (CMF leads to A). C was given at 50 mg/m2, po, days 1-14; M at 20 mg/m2, F at 300 mg/m2, and A at 20 mg/m2, iv, days 1 and 8 of each 28-day cycle. The response rates for CAMF vs. CMF did not differ significantly (complete and partial responses-62% vs. 49%; stabilizations-23% vs. 31%). Responses by site of metasis, median times to progression and median survivals were similar for both groups. Poor and good risk partial responders had similar survivals. Twelve percent of CMF patients treated with Adriamycin at the time of progression had partial responses with an associated improved survival. Since CMF is as effective as CAMF, but has less toxicity, low dose therapy with CMF is more acceptable than CAMF as an initial chemotherapy regimen for metastatic breast cancer. Adriamycin may be reserved for subsequent regression induction.


Angiotensin II induces DNA damage via AT1 receptor and NADPH oxidase isoform Nox4.
Epidemiological studies revealed increased renal cancer incidences and higher cancer mortalities in hypertensive individuals. Activation of the renin-angiotensin-aldosterone system leads to the formation of reactive oxygen species (ROS). In vitro, in renal cells, and ex vivo, in the isolated perfused mouse kidney, we could show DNA-damaging potential of angiotensin II (Ang II). Here, the pathway involved in the genotoxicity of Ang II was investigated. In kidney cell lines with properties of proximal tubulus cells, an activation of NADPH oxidase and the production of ROS, resulting in the formation of DNA strand breaks and micronuclei induction, was observed. This DNA damage was mediated by the Ang II type 1 receptor (AT1R), together with the G protein G ( α-q/11 ) . Subsequently, phospholipase C (PLC) was activated and intracellular calcium increased. Both calcium stores of the endoplasmic reticulum and extracellular calcium were involved in the genotoxicity of Ang II. Downstream, a role for protein kinase C (PKC) could be detected, because its inhibition hindered Ang II from damaging the cells. Although PKC was activated, no involvement of its known target, the NADPH oxidase isoform containing the Nox2 subunit, could be found, as tested by small-interfering RNA down-regulation. Responsible for the DNA-damaging activity of Ang II was the NADPH oxidase isoform containing the Nox4 subunit. In summary, in kidney cells the DNA-damaging activity of Ang II depends on an AT1R-mediated activation of NADPH oxidase via PLC, PKC and calcium signalling, with the NADPH subunit Nox4 playing a crucial role.


Short DNA fragments without sequence similarity are initiation sites for replication in the chromosome of the yeast Yarrowia lipolytica.
We have previously shown that both a centromere (CEN) and a replication origin are necessary for plasmid maintenance in the yeast Yarrowia lipolytica (). Because of this requirement, only a small number of centromere-proximal replication origins have been isolated from Yarrowia. We used a CEN-based plasmid to obtain noncentromeric origins, and several new fragments, some unique and some repetitive sequences, were isolated. Some of them were analyzed by two-dimensional gel electrophoresis and correspond to actual sites of initiation (ORI) on the chromosome. We observed that a 125-bp fragment is sufficient for a functional ORI on plasmid, and that chromosomal origins moved to ectopic sites on the chromosome continue to act as initiation sites. These Yarrowia origins share an 8-bp motif, which is not essential for origin function on plasmids. The Yarrowia origins do not display any obvious common structural features, like bent DNA or DNA unwinding elements, generally present at or near eukaryotic replication origins. Y. lipolytica origins thus share features of those in the unicellular Saccharomyces cerevisiae and in multicellular eukaryotes: they are discrete and short genetic elements without sequence similarity.


Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure.
Primary antiphospholipid antibody syndrome (PAPS) is an established cause of recurrent pregnancy loss, traditionally presumed to be due to 'intraplacental thromboses'. This study examines products of conception (POC) from early pregnancy failures to investigate the mechanism of pregnancy loss. POC from patients attending a recurrent miscarriage clinic and from terminations of pregnancy for non-medical reasons were examined histologically with particular regard to the presence or absence of vascular or intervillous thromboses and decidual endovascular trophoblast invasion. There were 31 PAPS-positive, 50 PAPS-negative, 34 aneuploid and 20 control cases at 6-14 weeks gestation. Villous morphology and frequency of intervillous thrombosis were not different among groups. Normal intradecidual endovascular trophoblast invasion was identified significantly less frequently in PAPS+ cases (24%), compared with controls (75%), aneuploid (53%), or PAPS- cases (61%; Z = -3.0, P < 0.01). In all cases there was apparently normal interstitial extravillous trophoblast invasion. Defective decidual endovascular trophoblast invasion, rather than excessive intervillous thrombosis, is the most frequent histological abnormality in PAPS+ associated early pregnancy loss. Furthermore, endovascular trophoblast invasion is not significantly reduced in the majority of fetal aneuploidy-associated pregnancy failures.


[The importance of screening for hepatitis B surface antigens in pregnancy].
Transmission of hepatitis B virus (HBV) from mother to infant during the perinatal period represents very efficient mode of HBV infection and often leads to severe long-term sequelae. Perinatal transmission can occur when an infant is born to mother positive for hepatitis B surface antigen (HBsAg), frequency of transmission is high if the mother is also HBeAg positive. Prevention of perinatal transmission of HBV is important since the majority of these infants who are infected at birth become chronic carriers and can subsequently develop chronic hepatitis, cirrhosis or primary hepatocellular carcinoma. Routine screening for HBsAg of all pregnant women attending prenatal clinic at the Institute for the Care of Mother and Child, Prague in the third trimester of pregnancy by Sevatest ELISA HBsAg Micro I. method (Sevac, Prague) began in June 1986. HBsAg positive patients were subsequently tested for HBeAg and anti-HBe hepatitis markers. Of the 2744 women examined 22 were found HBsAg positive, of these mostly asymptomatic carrier mothers 2 were positive for HBeAg, 14 for anti HBe and 6 were negative for both HBeAg and anti-HBe. All infants were given passive HBIG prophylaxis in conjunction with HB vaccine after birth regardless of HBeAg status of mother. At present no infant were found HBsAg positive at 6 month of age, observation of this risk group infants continues.


Oral Verruciform Xanthoma within Lichen Planus: A Case Report and Literature Review.
Verruciform xanthoma is an uncommon benign tumor, which exhibits a wide range of clinical patterns. The occurrence of the lesion in patients with immune-mediated mucocutaneous diseases may suggest a role of localized epithelial cell damage and chronic inflammation in its pathogenesis. A case of verruciform xanthoma on the tongue of a 56-year-old female with oral lichen planus is reported. An asymptomatic pink-white lesion with a granular surface was observed in the left lateral lingual border, which was closely associated with a white plaque and striae. An incisional biopsy was performed, and histologically, epithelial projections in a verrucous pattern were observed. In the subepithelial connective tissue, aggregates of foamy cells that exhibited immunoreactivity for CD68 were noted. The final diagnosis was verruciform xanthoma. The mucosa adjacent to the lesion demonstrated histopathological features consistent with lichen planus. A total of twelve cases of oral verruciform xanthomas in patients with oral lichen planus including the present case have been reported in the literature. The clinician should be aware that verruciform xanthoma may mimic malignancy, and therefore, biopsy is required for definitive diagnosis to be established, especially when this tumor develops within conditions that show potential for malignant transformation.


Changes in Th1/Th2 cytokine balance in Graves' disease.
Graves' disease (GD) is characterised by hyperthyroidism, caused by stimulatory thyrotropin receptor (TSHR) antibodies. Recent research shows that an important factor in the pathogenesis of autoimmune diseases is the change in the balance between Th1 cytokines, which promote cell mediated immunity, and Th2 cytokines, which promote humoral immunity. There are contradictory data about this balance shift in GD. Our objective was to determine the Th1/Th2 cytokine balance shift in patients with newly diagnosed GD, when compared to the same balance in healthy controls. We isolated mononuclear cells (MNC) from the peripheral blood of healthy donors and from patients with newly diagnosed GD before treatment. The MNC were activated with ionomycin in combination with phorbol 12-myristate 13-acetate (PMA). After 40-hour incubation, the concentrations of the cytokines produced (IFN-gamma, IL-4, IL-10, IL-12) in the culture supernatants were measured by ELISA (Endogen, USA). The MNC cultures from patients with GD produced significantly less IL-12 and significantly more IL-10 and IL-4 than MNC cultures from healthy controls. All calculated ratios of Th1 against Th2 cytokines in MNC cultures from patients with GD were significantly lower than in MNC cultures from healthy controls. Our results show a systemic shift of cytokine production in patients with GD toward the Th2 cytokine response, thus confirming the key role of TSHR antibodies and humoral immunity in the pathogenesis of GD.


Impact of acutely behavioural disturbed patients in the emergency department: A prospective observational study.
The present study describes patients with acute behavioural disturbance presenting to the ED, the impact they have on the department and any complications that occur. We performed a prospective observational study of adult patients (>17 years old) requiring parenteral sedation for acute behavioural disturbance over a 13 month period. Demographic data, mode of arrival, indication, drug type and dosing used for sedation were collected. Departmental data were recorded including the staff type and numbers involved and the condition of the department. The main outcomes were complications from sedative medication and injury sustained to patients or staff. Over the study period 173 patients met inclusion criteria, the majority (n = 104, 60%) were men with a mean age of 38.5 years (standard deviation 14.4); 51% of patients had more than one indication for sedation (n = 89), the commonest being mental health related plus drug intoxication (n = 30, 33.7%). Intoxication was frequently from either alcohol (n = 62, 47%) or methamphetamine (n = 41, 31%). The median number of staff involved was 10 (interquartile range 8-12). Staff members received an injury in 12% (n = 20) of sedations, with only 1% (n = 2) of patients receiving any physical injury; 12% (n = 20) had a minor complication from the sedation medication. No patient had any major complication (apnoea, intubation, arrhythmias or cardiac arrest). Patients with acute behavioural disturbance often have a history of mental illnesses and are commonly intoxicated. These patients have impacts on healthcare resources and pose risks to staff safety, but significant complications to patients do not occur frequently.


Development of an Athlete Diet Index for Rapid Dietary Assessment of Athletes.
Food-based diet indices provide a practical, rapid, and inexpensive way of evaluating dietary intake. Rather than nutrients, diet indices assess the intake of whole foods and dietary patterns, and compare these with nutrition guidelines. An athlete-specific diet index would offer an efficient and practical way to assess the quality of athletes' diets, guide nutrition interventions, and focus sport nutrition support. This study describes the development and validation of an Athlete Diet Index (ADI). Item development was informed by a review of existing diet indices, relevant literature, and in-depth focus groups with 20 sports nutritionists (median of 11 years' professional experience) from four elite athlete sporting institutes. Focus group data were analyzed (NVivo 11 Pro; QSR International Pty. Ltd., 2017, Melbourne, Australia), and key themes were identified to guide the development of athlete-relevant items. A modified Delphi survey in a subgroup of sports nutritionists (n = 9) supported item content validation. Pilot testing with athletes (n = 15) subsequently informed face validity. The final ADI (n = 68 items) was categorized into three sections. Section A (n = 45 items) evaluated usual intake, special diets or intolerances, dietary habits, and culinary skills. Section B (n = 15 items) assessed training load, nutrition supporting training, and sports supplement use. Section C (n = 8 items) captured the demographic details, sporting type, and caliber. All of the athletes reported the ADI as easy (40%) or very easy (60% of participants) to use and rated the tool as relevant (37%) or very relevant (63% of participants) to athletes. Further evaluation of the ADI, including the development of a scoring matrix and validation compared with established dietary methodology, is warranted.


Tunable and Lightweight On-Chip Event Detection for Implantable Bladder Pressure Monitoring Devices.
Lower urinary tract dysfunctions, such as urinary incontinence and overactive bladder, are conditions that greatly affect the quality of life for millions of individuals worldwide. For those with more complex pathophysiologies, diagnosis of these conditions often requires a urodynamics study, providing physicians with a snapshot view of bladder mechanics. Recent advancements in implantable bladder pressure monitors and advanced data analysis techniques have made diagnosis through chronic monitoring a promising prospect. However, implants targeted at treatment must remain in the bladder for long periods of time, making minimizing power consumption a primary design objective. Currently, much of the typical implant's power draw is due to data transmission. Previous work has demonstrated an adaptive rate transmission technique to reduce power consumption. However, the ultimate reduction in power consumption can only be attained when the device does not transmit bladder pressure samples, but rather bladder events. In this paper, we present an algorithm and circuit level implementation for on-chip bladder pressure data compression and event detection. It is designed to be a complete, tunable, and lightweight diagnosis and treatment framework for bladder pressure monitoring implants, capable of selectively transmitting compressed bladder pressure data with tunable quality, "snapshots" of significant bladder events, or simply indicate events occurred for the highest energy efficiency. The design aims to minimize area through resource reuse, leading to a total area of 1.75 , and employs advanced VLSI techniques for power reduction. With compression and event detection enabled, the design consumes roughly 2.6 nW in TSMC technology. With only event detection, this reduces to 2.1 nW, making this approach ideal for long-life implantable bladder pressure monitoring devices.


Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. British Association for Psychopharmacology.
A revision of the British Association for Psychopharmacology guidelines for treating depressive disorders with antidepressants was undertaken in order to specify the scope and target of the guidelines and to update the recommendations based explicitly on the available evidence. A consensus meeting, involving experts in depressive disorders and their treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from participants and interested parties. A literature review is given which identifies the quality of evidence followed by recommendations, the strength of which are based on the level of evidence. The guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing, management when initial treatment fails, continuation treatment, maintenance treatment to prevent recurrence and stopping treatment.


Distribution and abundance of natural parasitoid (Hymenoptera: Pteromalidae) populations of house flies and stable flies (Diptera: Muscidae) at the University of Florida Dairy Research Unit.
From September 2001 through September 2002, house fly and stable fly pupae were collected weekly from three fly habitats at the University of Florida Research dairy in northcentral Florida and evaluated for parasitism. Varying parasitism percentages were observed throughout the study but they were not affected by temperature, precipitation or fly abundance. Of the 6,222 house fly pupae and 1,660 stable fly pupae that produced either a host fly or a parasitoid, 26.9% and 26.7% were parasitized, respectively. Ten parasitoid species were recovered, with the genus Spalangia accounting for 85.7% of the total; the most common parasitoids attacking house fly and stable fly pupae were Spalangia endius Walker (33.9% and 27.3%), S. cameroni Perkins (27.9% and 40.6%), and S. nigroaenea Curtis (21.0% and 24.8%), respectively. Other parasitoids included one specimen of S. erythromera Förster and four specimens of Phygadeuon fumator Gravenhörst (Ichneumonidae). The percentage parasitism of pupae collected from bunker silos was higher than that of pupae from calf pens and open pastures. Spalangia cameroni was consistently recovered through the entire year. Spalangia nigroaenea was predominant in July, August, and September. Spalangia endius was most active from October to May with a peak of relative abundance in January.


Noise and laboratory animals.
The preponderance of experimental evidence gathered over the past three decades indicates that exposure to intense noise can lead to a wide variety of functional and structural changes in laboratory animals. Although little information regarding noise effects at more moderate levels is available, the range of intensities at which such effects begin to be manifested in humans seems to be present in animal quarters. Fortunately, there is an assortment of techniques for reducing the noise exposure of both animals and animal care personnel. Because of serious deficiencies in our knowledge concerning actual long-term noise levels in animal housing facilities and the ways in which such noise affects different species, the imposition at this time of quantitative regulations governing exposure limits for laboratory animals would be premature.


[Use of 5-phosphodiesterase inhibitors in patients with LUTS secondary to BPH: our experience and review of the literature].
The phosphodiesterase inhibitors are used in the treatment of ED and there are increasing data of effects of these drugs on bladder and urethral relaxation as well as of prostatic smooth muscles that may relief the symptoms of BPH. This study was conducted to evaluate the role of Tadalafil (a PDE-5 inhibitor) in combination with standard therapy for the treatment of BPH. In this randomized clinical trial of 165 patients with obstructive and irritative urinary tract symptoms due to BPH, IPSS ≥8, Iief ≥11, Q-max from 5 mL/s to 15 mL/s and residual urine volume (RUV) <120 mL, there was indication for surgical intervention. These patients were randomly allocated in three groups. Each patient received a therapeutic treatment daily for 12 weeks. Group A received treatment with tamsulosin 0.4 mg and tadalafil 5 mg, Group B received a standard treatment with tamsulosin 0.4 mg for BPH and Group C received only one treatment with tadalafil 5 mg. There was no significant difference in terms of IPSS score, Qmax and RUV before treatment in the three groups tested. Analysis of the data shows that in patients treated with tamsulosin and tadalafil IPSS, IIEF and QoL were significantly improved in a different way than in the other two groups, while the Qmax and RUV did not show a significant change in the three groups, remaining almost constant. The PDE-5 inhibitor improves quality of life and urinary symptoms in patients with LUTS suggestive of BPH, but doesn't have any significant effect on Qmax and RUV.


(+)-Borneol improves the efficacy of edaravone against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway.
Compound edaravone injection (C.EDA), a compound preparation composed of edaravone (EDA) and (+)-Borneol with the mass ratio of 4: 1, displays a better anti-inflammatory activity than EDA. However, its precise mechanism remains to be further studied. In this work, we investigated whether (+)-Borneol could improve the efficacy of EDA against DSS-induced colitis. We found that C.EDA at 7.5 and 15mg/kg could significantly relieve the disease activity index (DAI) and reduce the loss of body weight and colon length in a dose-dependent manner, while EDA or (+)-Borneol alone only had moderate effects even at the highest dose. Additionally, ELISA revealed that C.EDA could more dramatically decrease the protein levels of inflammatory cytokines and increase the levels of anti-inflammatory cytokine than EDA or (+)-Borneol alone both in colon tissues and serum. H&E staining and IHC assay also indicated that C.EDA exhibited more prominent effects on increasing the population of M2 macrophages, decreasing M1 macrophages infiltration and protecting intestinal barrier integrity. Furthermore, in vitro studied demonstrated that C.EDA, EDA or (+)-Borneol failed in inhibiting M1 macrophages activation but could specifically induce the activation of M2 macrophages in a STAT3-dependent manner. Knockdown the expression of STAT3 successfully abolished the effect of C.EDA and EDA on promoting M2 macrophages activation. Consistent with in vivo study, C.EDA exhibited a more efficient ability of inducing M2 macrophages polarization and STAT3 activation than EDA or (+)-Borneol alone in vitro. In conclusion, we confirmed that (+)-Borneol improved the efficacy of EDA against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway.


Implications of growth surveys in social and curative pediatrics.
The main characteristics of children are growth, development, gradually building up of resistance and decrease of vulnerability. The biometric parameters of choice for a general medical assessment of growth and (physical) development are attained height, weight for height, at infancy and pre-school age neuro-motoric development, and at adolescence the successive stages of secondary sex characteristics. In 1955, 1965, and 1980 nation-wide representative growth and development surveys were performed in the Netherlands. The results of such studies serve multiple purposes: they provide reference data for individual medical assessment, and contribute to the description of the health situation of the population by the study of secular changes. The data are also in use in the construction of our living environment and may supply a biological basis for governments policies concerning young people.


Mental health care as delivered by Dutch general practitioners between 2004 and 2008.
In the field of mental health care, a major role for general practice is advocated. However, not much is known about the treatment and referral of mental health problems in general practice. This study aims at the volume and nature of treatment of mental health problems in general practice; the degree to which treatment varies according to patients' gender, age, and social economic status; and trends in treatment and referral between 2004 and 2008. Descriptive study with trends in time in general practice in the Netherlands. 350,000 patients enlisted in general practice, whose data from the Netherlands Information Network of General Practice were routinely collected from 1 January 2004 to 31 December 2008. For all episodes of mental health problems recorded by the GP, the proportion of patients receiving prolonged attention, medication, and referral during each year have been calculated. More than 75% of patients with a recorded mental health problem received some kind of treatment, most often medication. In 15-20% of cases medication was accompanied by prolonged attention; 9-13% of these patients were referred (given referrals), the majority to specialized mental health care. Age is the most important variable associated with treatment received. During the period 2004-2008, treatment with medication declined slightly and referrals increased slightly. Treatment for psychological disorders is mostly delivered in general practice. Although in recent years restraint has been advocated in prescribing medication and collaboration between primary and secondary care has been recommended, these recommendations are only partially reflected in the treatment provided.


Potential of the Antibody Against cis-Phosphorylated Tau in the Early Diagnosis, Treatment, and Prevention of Alzheimer Disease and Brain Injury.
Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) share a common neuropathologic signature-neurofibrillary tangles made of phosphorylated tau-but do not have the same pathogenesis or symptoms. Although whether traumatic brain injury (TBI) could cause AD has not been established, CTE is shown to be associated with TBI. Until recently, whether and how TBI leads to tau-mediated neurodegeneration was unknown. The unique prolyl isomerase Pin1 protects against the development of tau-mediated neurodegeneration in AD by converting the phosphorylated Thr231-Pro motif in tau (ptau) from the pathogenic cis conformation to the physiologic trans conformation, thereby restoring ptau function. The recent development of antibodies able to distinguish and eliminate both conformations specifically has led to the discovery of cis-ptau as a precursor of tau-induced pathologic change and an early driver of neurodegeneration that directly links TBI to CTE and possibly to AD. Within hours of TBI in mice or neuronal stress in vitro, neurons prominently produce cis-ptau, which causes and spreads cis-ptau pathologic changes, termed cistauosis. Cistauosis eventually leads to widespread tau-mediated neurodegeneration and brain atrophy. Cistauosis is effectively blocked by the cis-ptau antibody, which targets intracellular cis-ptau for proteasome-mediated degradation and prevents extracellular cis-ptau from spreading to other neurons. Treating TBI mice with cis-ptau antibody not only blocks early cistauosis but also prevents development and spreading of tau-mediated neurodegeneration and brain atrophy and restores brain histopathologic features and functional outcomes. Thus, cistauosis is a common early disease mechanism for AD, TBI, and CTE, and cis-ptau and its antibody may be useful for early diagnosis, treatment, and prevention of these devastating diseases.


Weight, gender, and snack appeal.
In this study, we hypothesized that overweight/obese persons have an exaggerated approach tendency toward high calorie foods. Testing this hypothesis, a stimulus response compatibility (SRC) task was used to assess approach-avoidance tendencies toward food in both overweight/obese participants (n=42), and normal weight controls (n=46). The SRC task is a reaction time task measuring how fast one approaches and avoids pictures of food and non-foods according to given instructions. It was found that overweight/obese men are slower at avoiding particularly high calorie snack foods. But this does not appear to be the case for overweight/obese women who showed nearly as fast avoidance as approach toward the high calorie food cues. It is concluded that overweight/obese women, rather than men, are ambivalent toward high calorie foods, which is the likely result of high dietary restraint.


Androgen increases AT1a receptor expression in abdominal aortas to promote angiotensin II-induced AAAs in apolipoprotein E-deficient mice.
Castration of male apolipoprotein E-deficient (apoE-/-) mice reduces angiotensin II (Ang II)-induced abdominal aorta aneurysms (AAAs) to that of female mice. The purpose of this study was to determine whether this reduction is attributable to androgen-mediated regulation of aortic Ang II type 1A receptors (AT1aR). AT1aR mRNA abundance in the AAA-prone region of abdominal aortas was 8-fold greater compared to thoracic aortas of male but not female mice. AT1aR mRNA abundance decreased after castration in abdominal but not thoracic aortas of male mice. Dihydrotestosterone (DHT, 0.16 mg/d) administration to castrated male mice restored AT1aR mRNA abundance in abdominal aortas but had no effect in thoracic aortas. DHT also increased AT1aR mRNA abundance in abdominal aortas from female mice. Castrated male or female apoE-/- mice were administered DHT during infusion of saline or Ang II (1000 ng/kg/min for 28 days). DHT administration did not alter serum cholesterol concentrations, lipoprotein distributions, or atherosclerotic lesion areas in either male or female mice. However, administration of DHT increased AAA incidence in male (27% placebo versus 75% DHT) and female mice (28% placebo versus 64% DHT). Androgen promotes AT1aR mRNA abundance in abdominal aortas associated with increased Ang II-induced AAAs.


Placenta-Specific Protein 1 Expression in Human Papillomavirus 16/18-Positive Cervical Cancers Is Associated With Tumor Histology.
Expression of the trophoblast-specific gene placenta-specific protein 1 (PLAC1) has been detected in a wide variety of cancers. However, to date, PLAC1 expression has not been shown in cervical cancer. We have carried out a preliminary study that shows for the first time that PLAC1 is expressed in cervical cancers. A total of 16 primary cervical tumors were obtained from patients shown to be human papillomavirus (HPV) 16/18 positive. Total cellular RNA, genomic DNA, and total protein were purified from each tumor. These materials were then used to determine PLAC1 expression, TP53 mutation status, and p53 expression. The PLAC1 expression was demonstrated in all 16 primary cervical tumors. The highest levels of expression were found in the more aggressive squamous and adenosquamous histologic types compared with adenocarcinomas. Moreover, the proportion of total PLAC1 message coming from the P1 promoter, also termed the distal or cancer promoter, was significantly greater in the more aggressive squamous and adenosquamous histologic types compared with adenocarcinomas. Finally, in spite of all 16 tumors being HPV-16/18 positive, 3 of 8 squamous cell cancers and 2 of 5 adenocarcinomas expressed wild-type p53 protein. Consistent with the recently shown suppression of the PLAC1P1 promoter by wild-type p53, these p53 positive tumors displayed among the lowest P1-specific PLAC1 expression levels. The PLAC1 expression has been demonstrated for the first time in cervical cancers. This preliminary study has further revealed a complex relationship between PLAC1 expression, cervical cancer histologic type, p53, and HPV type that requires further investigation.


Newborn weight nomograms in selected low and middle-income countries.
Growth impairment is common in low- and middle-income countries (LMIC) and may begin during early infancy, increasing morbidity and mortality. To ensure healthy infant growth, healthcare providers in high-income countries (HIC) track newborn weight change using tools developed and validated in HIC. To understand the utility of these tools for LMIC, we conducted a secondary analysis to compare weight trajectories in the first 5 days of life among newborns born in our LMIC cohort to an existing HIC newborn weight tool designed to track early weight change. Between April 2019 and March 2020, a convenience sample of 741 singleton healthy breastfeeding newborns who weighed ≥ 2000 g at birth were enrolled at selected health facilities in Guinea-Bissau, Nepal, Pakistan, and Uganda. Using a standardized protocol, newborn weights were obtained within 6 h of birth and at 1, 2, 3, 4, and 5 days, and nomograms depicting newborn weight change were generated. The trajectories of early newborn weight change in our cohort were largely similar to published norms derived from HIC infants, with the exceptions that initial newborn weight loss in Guinea-Bissau was more pronounced than HIC norms and newborn weight gain following weight nadir was more pronounced in Guinea-Bissau, Pakistan, and Uganda than HIC norms. These data demonstrate that HIC newborn weight change tools may have utility in LMIC settings.


[Activity of peptidyl-dipeptidase A and carboxypeptidase N in the serum of patients with Alzheimer disease].
The activity of peptidyl-dipeptidase A and carboxypeptidase N taking part in peptide metabolism in the serum of patients with Alzheimer disease were studied. The role of these enzymes in the metabolism of neuropeptides and beta-amyloid at the Alzheimer disease was discussed.


Improving parenting in families referred for child maltreatment: a randomized controlled trial examining effects of Project Support.
Project Support is an intervention designed to decrease coercive patterns of aggressive discipline and increase positive parenting. This research evaluates Project Support in a sample of families reported to Children's Protective Services (CPS) for allegations of physical abuse or neglect; 35 families with a child between 3- and 8-years-old participated. In all families, CPS allowed the children to remain in the family home while the family received services. Families were randomly assigned to receive either Project Support or services as usual, which were provided by CPS or CPS-contracted service providers. To evaluate intervention effects, a multimethod, multi-informant assessment strategy was used that included data from mothers' reports, direct observation of parents' behavior, and review of CPS records for re-referrals for child maltreatment. Families who received Project Support services showed greater decreases than families who received services as usual in the following areas: mothers' perceived inability to manage childrearing responsibilities, mothers' reports of harsh parenting, and observations of ineffective parenting practices. Only 5.9% of families in the Project Support condition had a subsequent referral to CPS for child maltreatment, compared with 27.7% of families in the comparison condition. The results suggest that Project Support may be a promising intervention for reducing child maltreatment among families in which it has occurred.


De novo post-pollen mitosis II tobacco pollen tube transcriptome.
In our previous study we applied the Agilent 44K tobacco gene chip to introduce and analyze the tobacco male gametophyte transcriptome in mature pollen and 4h pollen tubes. Here we extended our analysis post-pollen mitosis II (PMII) by including a new data set obtained from more advanced stage of the ongoing progamic phase - pollen tubes cultivated in vitro for 24 h. Pollen mitosis II marks key events in the control of male gametophyte development, the production of two sperm cells. In bicellular species covering cca 70% of angiosperms including Nicotiana tabacum, PMII takes place after pollen germination in growing pollen tube. We showed the stable and even slightly increasing complexity of tobacco male gametophyte transcriptome over long period of progamic phase-24 h of pollen tube growth. We also demonstrated the ongoing transcription activity and specific transcript accumulation in post-PMII pollen tubes cultivated in vitro. In all, we have identified 320 genes (2.2%) that were newly transcribed at least after 4h of pollen tube cultivation in vitro. Further, 699 genes (4.8%) showed over 5-fold increased accumulation after the 24h of cultivation.


Barbiturate-induced alterations in the kinetic parameters of slow outward current in Aplysia giant neurons.
Regulation of spike frequency adaptation has been postulated to be a neuronal mechanism of action of the barbiturates (Zbicz and Wilson, 1981). A barbiturate sensitive slow outward current is present in Aplysia giant neurons, and this current is very effective at regulating adaptation. In the current study a quantitative method of determining the effect of barbiturates was developed using a single-electrode voltage clamp. This method, tail current analysis, involved measuring the exponential decay of the slow outward current at the end of a depolarizing voltage-clamp command. The tail currents were made up of two decay phases with average half-times of 7 and 70 sec, and the tail current amplitude accurately reflected the magnitude of slow outward current. Barbiturates were found to cause a concentration-related, saturable and stereospecific increase in one component of the tail currents, the amplitude of the slow phase. With moderate concentrations of barbiturates there were no changes in the other parameters describing the exponential decay current. The rank order of potency of barbiturates for the enhancement of slow outward current was not well correlated with the lipid solubility of these drugs, indicating that slow outward current enhancement is not due to a nonspecific mechanism, but rather may be receptor mediated.


Progressive hydrocephalus despite early complete reversal of hindbrain herniation after prenatal open myelomeningocele repair.
Open prenatal myelomeningocele (MMC) repair is typically associated with reversal of in utero hindbrain herniation (HBH) and has been posited to be associated with a reduction in both postoperative prenatal and immediate postnatal hydrocephalus (HCP) risks. However, the long-term postnatal risk of HCP following HBH reversal in these cases has not been well defined. The authors describe the results of a long-term HCP surveillance in a cohort of patients who underwent prenatal MMC repair at their institution. A retrospective review of all prenatal MMC repair operations performed at the Mayo Clinic between 2012 and 2017 was conducted. Pertinent data regarding the clinical courses of these patients before and after MMC repair were summarized. Outcomes of interest were occurrences of HBH and HCP and the need for intervention. A total of 9 prenatal MMC repair cases were identified. There were 7 cases in which MRI clearly demonstrated prenatal HBH, and of these 86% (6/7) had evidence of HBH reversal after repair and prior to delivery. After a mean postnatal follow-up of 20 months, there were 3 cases of postnatal HCP requiring intervention. One case that failed to show complete HBH reversal after MMC repair required early ventriculoperitoneal shunting. The other 2 cases were of progressive, gradual-onset HCP despite complete prenatal HBH reversal, requiring endoscopic third ventriculostomy with choroid plexus cauterization at ages 5 and 7 months. Although prenatal MMC repair can achieve HBH reversal in a majority of well-selected cases, the prevention of postnatal HCP requiring intervention appears not to be predicated on this outcome alone. In fact, it appears that in a subset of cases in which HBH reversal is achieved, patients can experience a progressive, gradual-onset HCP within the 1st year of life. These findings support continued rigorous postnatal surveillance of all prenatal MMC repair patients, irrespective of postoperative HBH outcome.


Analysis on Intraoperative Electrocorticogram Characteristics for Evaluating the Risk of Postoperative Epilepsy.
Epilepsy is one of the most common complications after craniotomy, which happens suddenly and does great harm. There still lacks of effective prediction method during the operation. The main purpose of this paper is to explore the correlation between the characteristics of intraoperative electrocorticogram (ECoG) and postoperative epilepsy, and select effective features to establish a prediction model. This retrospective study uses intraoperative ECoG recordings of 144 patients with cerebrovascular diseases undergoing cerebral revascularization surgeries. The cases are divided into subtypes of ischemic and hemorrhagic. Nine types of ECoG features are designed on different frequency bands indicating clinical information, power spectrum, complexity, sequence change, and information quantity, while their changes in different surgical stages are also considered. Then statistical analysis is used to obtain features significantly related to postoperative epilepsy (p<0.05). The sparse representation method is used on these features to further screen and reduce the redundancy, and then machine learning methods are used to establish a prediction model for postoperative epilepsy. The accuracy, sensitivity and specificity of the best prediction model can achieve 0.817, 0.800 and 0.833 respectively under 5-fold cross validation.Clinical Relevance-This study explores the correlation between the characteristics of intraoperative ECoG and postoperative epilepsy, investigates the possibility to use the ECoG features and machine learning algorithms to assess the risk of postoperative epilepsy during the surgery. Further results are expected to provide reference for preventive measures to reduce the occurrence of postoperative epilepsy.


Exploring changes over time in habilitation professionals' perceptions and applications of the International Classification of Functioning, Disability and Health, version for Children and Youth (ICF-CY).
This study explored how professionals in inter-disciplinary teams perceived the implementation of the World Health Organization's International Classification of Functioning, Disability and Health, version for Children and Youth (ICF-CY) in Swedish habilitation services. Descriptive longitudinal mixed-methods design. Following participation in a 2-day in-service training on the ICF-CY, 113 professionals from 14 interdisciplinary teams described their perceptions of the implementation of the ICF-CY at 3 consecutive time-points: during in-service training, after 1 year, and after 2.5 years. Implementation of the ICF-CY in daily work focused on assessment and habilitation planning and required adaptations of routines and materials. The ICF-CY was perceived as useful in supporting analyses and in communication about children's needs. Professionals also perceived it as contributing to new perspectives on problems and a sharpened focus on participation. Professionals indicated that the ICF-CY enhanced their awareness of families' views of child participation, which corresponded to organizational goals for habilitation services. An implementation finding was a lack of tools fitting the comprehensive ICF-CY perspective. The study points to the need for ICF-CY-based assessment and intervention methods focusing on child participation.


The combined latissimus dorsi-scapular free flap in head and neck reconstruction.
Microvascular free tissue transfer techniques offer great versatility in the selection of tissue for reconstruction of head and neck defects. The system of flaps based on the subscapular artery and vein provides the widest array of composite free flaps. The possible flaps that can be harvested based on this single vascular pedicle include the scapular and parascapular skin flaps, the serratus anterior and latissimus dorsi muscle flaps, and the lateral scapular bone flap. In addition, a segment of vascularized rib can be transferred with the serratus anterior and latissimus dorsi muscles. Large cutaneous defects can be resurfaced by combining the latissimus dorsi and scapular flaps. Another advantage of this combined flap is the independent vascular pedicles of its components, which allow freedom in orientation of the various tissue segments. Thus, the combined flap can be helpful in reconstructing complex three-dimensional composite defects of the head and neck. In addition, by reinnervating the muscle portions of this flap, bulk can be preserved and an improved functional reconstruction of the oral cavity achieved. A review of the literature shows three previous reports utilizing this combination of flaps in five patients. We report the use of the combined latissimus dorsi-scapular free flap in six patients to reconstruct massive composite defects of the oral cavity, midface, and scalp. There was one flap failure, which was successfully reconstructed with the contralateral latissimus dorsi-scapular flap. The anatomy of this flap is reviewed, and the indications for its application are discussed.


Self-assembly of patterned monolayers with nanometer features: molecular selection based on dipole interactions and chain length.
Patterned cocrystal monolayers self-assemble on HOPG in contact with solutions containing complementary pairs of 1,5-chain-substituted anthracene derivatives. Monolayer unit cells containing three or four molecules and spanning 9-11 nm are generated. The monolayers consist of alternating aromatic and aliphatic columns. The designs and dimensions of the cocrystal patterns (unit cells) are determined by (i) the preferred packing alignment of identical length side chains, (ii) the selectivity of each side chain for neighboring chains, (iii) the identities of the two side chains on each anthracene, and (iv) the 2D-chirality of 1,5-substituted anthracenes. The aliphatic columns form by interdigitation of identical length side chains arrayed in an antiparallel alignment, with the nth heavy atom of one side chain in registration with the (omega+2-n)th heavy atom of two adjacent chains ((omega <--> 2) packing). Adjacent side chains are attached, alternately, to anthracenes in one of the two flanking aromatic columns. The preference for (omega <--> 2) packing optimizes side-chain van der Waals interactions. The composition and fidelity of patterning in the cocrystal monolayers requires an additional source of "molecular recognition" in addition to side-chain length. Dipolar interactions, both attractive and repulsive, between ether groups in neighboring, (omega <--> 2) packed side chains, constitute a second recognition element needed for cocrystal self-assembly.


Calculation of electric fields in a multiple cylindrical volume conductor induced by magnetic coils.
A method is presented for calculating the electric field, that is induced in a cylindrical volume conductor by an alternating electrical current through a magnetic coil of arbitrary shape and position. The volume conductor is modeled as a set of concentric, infinitely long, homogeneous cylinders embedded in an outer space that extends to infinity. An analytic expression of the primary electric field induced by the magnetic coil, assuming quasi-static conditions, is combined with the analytic solution of the induced electric scalar potential due to the inhomogeneities of the volume conductor at the cylindrical interfaces. The latter is obtained by the method of separation of variables based on expansion with modified Bessel functions. Numerical results are presented for the case of two cylinders representing a nerve bundle with perineurium. An active cable model of a myelinated nerve fiber is included, and the effect of the nerve fiber's undulation is shown.


Anatomical variations in the left coronary artery and its branches.
Proficiency in the anatomy of coronary arteries and their variations is important for proper interpretation of coronary angiographies. The left coronary artery (LCA) commonly originates at the level of the left posterior aortic sinus and normally bifurcates into the anterior interventricular artery and circumflex artery. This study aimed to determine the variations in the LCA and its branches. The study was conducted on 30 heart specimens. We observed the origin, length and branching pattern of the LCA and its coronary dominance. We found a short main LCA trunk in three specimens and a long main LCA trunk in one specimen. In two specimens, the division of the LCA led to three branches. With regard to 'dominance', one specimen showed left dominance while another showed codominance. Variations of the LCA are clinically relevant, especially when a perioperative coronary perfusion or coronary arteriography is performed.


Synthesis of aqueous Au core-Ag shell nanoparticles using tyrosine as a pH-dependent reducing agent and assembling phase-transferred silver nanoparticles at the air-water interface.
We demonstrate that the amino acid tyrosine is an excellent reducing agent under alkaline conditions and may be used to reduce Ag+ ions to synthesize stable silver nanoparticles in water. The tyrosine-reduced silver nanoparticles may be separated out as a powder that is readily redispersible in water. The silver ion reduction at high pH occurs due to ionization of the phenolic group in tyrosine that is then capable of reducing Ag+ ions and is in turn converted to a semi-quinone structure. These silver nanoparticles can easily be transferred to chloroform containing the cationic surfactant octadecylamine by an electrostatic complexation process. The now hydrophobic silver nanoparticles may be spread on the surface of water and assembled into highly ordered, linear superstructures that could be transferred as multilayers onto suitable supports by the versatile Langmuir-Blodgett technique. Further, tyrosine molecules bound to the surface of Au nanoparticles through amine groups in the amino acid may be used to selectively reduce silver ions at high pH on the surface of the Au nanoparticles, thus leading to a simple strategy for realizing phase-pure Au core-Ag shell nanostructures.


Proton-impact ionisation cross sections for nanodosimetric track structure simulations.
Monte Carlo simulations of the particle track structure require accurate ion- and electron-impact cross-section data of the medium. These data are scarce and often inconsistent when measured by different groups. In this work, literature data on ionisation cross sections (CSs) of nitrogen and propane for protons with energies 0.1-10 MeV are reviewed and implemented in the code PTra. Methane data were used to obtain proton-impact CSs of propane due to their absence in the literature. PTra is benchmarked by comparing simulated particle-track parameters to experimental results, measured with an ion-counting nanodosemeter.


Implications of hypnotic flexibility on patterns of clinical use.
Insomnia is common among the primary care patient population, 1.3 times more common in women than men, and the prevalence increases with age. Until recently, benzodiazepines (BZs) were the only first-line hypnotics, but with the availability of non-BZ sleep agents, the management of insomnia is changing. Zolpidem and zopiclone have adverse-effect profiles similar to BZs but lack next-day residual effects with bedtime dosing. Zaleplon is a fast-onset, rapidly eliminated medication that allows for dosing at bedtime or during the night with minimal concern for residual effects. In addition, the BZ-associated problems of tolerance and rebound effects are not evident with long-term zaleplon use. The pharmacokinetic profile of zaleplon has the potential to allow for the treatment of symptoms of sleeplessness when they occur, an approach that could replace the standard practice of always treating in anticipation of a problem.


Use of a Guided Imagery Mobile App (See Me Serene) to Reduce COVID-19-Related Stress: Pilot Feasibility Study.
The SARS-CoV-2 pandemic has led to concerns about mental health resulting from regional and national lockdowns, social isolation, job loss, and concern about disease exposure. We describe results of the pilot feasibility study of the See Me Serene mHealth app. The app provides users with immersive, vivid, nature experiences to reduce stress and anxiety related to COVID-19 and other isolation. The goals of the study were to develop the See Me Serene app and test the feasibility and acceptability of study procedures, and explore the potential impact of the app on stress and anxiety. We developed and tested the See Me Serene app and our study procedures for feasibility, and gathered preliminary data with a goal of 100 participants. The research was conducted in 2 phases: (1) development and internal testing of the app; and (2) feasibility and pilot testing with participants recruited online through earned media (eg, news stories), presentations at a university campus, and social media (eg, online sharing of earned media and presentations). The feasibility study employed a mixed methods, within-subjects, pre-/posttest design. At baseline and 30-day follow-up, we assessed stress-related variables via validated self-report measures and saliva samples for determination of cortisol concentrations. We met or surpassed all our feasibility benchmarks for recruitment (101 participants recruited), retention (91% [90/99] of 30-day assessment completed), and data collection (99 participants completed all baseline data; 85% [84/99] of salivary cortisol samples returned). Participants adhered to the intervention. On average, participants listened to 48.2 audio files over 30 days or approximately 1.6 audio files per day. Participants were satisfied with the app, with 87% (78/90) rating the app as helpful in dealing with stress and anxiety. The app showed the potential to reduce stress, anxiety, loneliness, and worry. We did not find significant differences (P=.41) in cortisol levels over time. Our findings suggest that future research is warranted to test the efficacy of the See Me Serene app with a representative, diverse sample. There is a need for evidence-based and easily disseminable stress-reduction interventions. See Me Serene is a feasible intervention and has the potential to reduce stress related to COVID-19 and other forms of social isolation. More research on See Me Serene is warranted.


A Practice-Based Research Network (PBRN) Roadmap for Evaluating COVID-19 in Community Health Centers: A Report From the OCHIN PBRN.
Primary care practice-based research networks (PBRNs) are critical laboratories for generating evidence from real-world settings, including studying natural experiments. Primary care's response to the novel coronavirus-19 (COVID-19) pandemic is arguably the most impactful natural experiment in our lifetime. EVALUATING THE IMPACT OF COVID-19: We briefly describe the OCHIN PBRN of community health centers (CHCs), its partnership with implementation scientists, and how we are leveraging this infrastructure and expertise to create a rapid research response evaluating how CHCs across the country responded to the COVID-19 pandemic. COVID-19 RESEARCH ROADMAP: Our research agenda focuses on asking: How has care delivery in CHCs changed due to COVID-19? What impact has COVID-19 had on the delivery of preventive services in CHCs? Which PBRN services (e.g., data surveillance, training, evidence synthesis) are most impactful to real-world practices? What decision-making strategies were used in the PBRN and its practices to make real-time changes in response to the pandemic? What critical factors in successfully and sustainably transforming primary care are illuminated by pandemic-driven changes? PBRNs enable real-world evaluation of practice change and natural experiments, and thus are ideal laboratories for implementation science research. We present a real-time example of how a PBRN Implementation Laboratory activated a response to study a historic natural experiment, to help other PBRNs charting a course through this pandemic.


Influence of Saccharomyces cerevisiae fermentation products, SmartCare in milk replacer and Original XPC in calf starter, on the performance and health of preweaned Holstein calves challenged with Salmonella enterica serotype Typhimurium.
This study was designed to investigate the effects of supplementing SmartCare (SC; Diamond V, Cedar Rapids, IA) in milk replacer and Original XPC (XPC; Diamond V) in calf starter on performance and health of preweaned calves following an oral challenge with Salmonella enterica. The study was performed in two 35-d periods with 30 Holstein bull calves (2 ± 1 d of age) per period. In each period, calves were blocked by location in the barn and randomly assigned to treatments that included control, base milk replacer and calf starter with no added Saccharomyces cerevisiae fermentation products; SC, milk replacer with 1 g of SC/calf per day and base calf starter; and SC+XPC, milk replacer with 1 g of SC/calf per day and calf starter with 0.5% XPC on a dry matter basis. Calves were fed 350 g of milk replacer solids at 14% dry matter twice daily at 0700 and 1700 h. Calf starter and water were offered ad libitum and intakes were recorded daily. Calves were challenged with 108 cfu of sulfamethazine-resistant Salmonella enterica serotype Typhimurium orally on d 14 of the study. Fecal Salmonella shedding was determined on d 14 to 21 (daily), 24, 28, and 35 using selective media. Blood samples were collected on d 0, 7, 14, 16, 18, 21, 24, 28, and 35 and analyzed for hematology; plasma were analyzed for haptoglobin concentrations. All data were reported as CON, SC, and SC+XPC, respectively. Calf starter intake was increased from d 22 to 35 among SC+XPC calves and from d 29 to 35 among SC calves. The SC+XPC calves had a lower neutrophil-to-lymphocyte ratio (0.81, 0.83, and 0.69 ± 0.051) throughout the study. The SC+XPC calves also had lower hematocrits (35.1, 35.3, and 33.4 ± 0.54%) and hemoglobin concentrations (10.8, 10.6, and 10.1 ± 0.16 mg/dL) throughout the study. We found a tendency for calves fed SC and SC+XPC to have more solid fecal scores during the week after the challenge. We observed no treatment or treatment × time differences on plasma haptoglobin concentrations (63, 48, and 60 ± 0.5 μg/mL). No treatment differences were observed in the fecal shedding of the Salmonella; however, we noted a tendency for a treatment difference in the percentage of calves positive for Salmonella present in the ileal tissue at d 21 after the challenge (25, 50, and 60%). Supplementing preweaned Holstein calves with both SC in milk replacer and XPC in calf starter improved starter intake and improved fecal consistency immediately after a mild Salmonella enterica challenge, but more data are needed to further understand how these yeast fermentation products influence the immune responses to Salmonella enterica.


[A summarized method for calculating the possibility of resorption of a focal lesion as a function of its volume and irradiation dose].
The mathematical model of calculation of equivalent conditions of irradiation (CECI) can be used in those cases, when it is impossible to divide clearly the tumor cells into radiation sensitive (RS) and radiation resistant (RR) and when the spectrum of radio-biological properties of tumor cells can be regarded as quasi-continuous.


Cationic liposomes as in vivo delivery vehicles.
Optimization of cationic liposomal complexes for in vivo applications is complex involving many diverse components. These components include nucleic acid purification, plasmid design, formulation of the delivery vehicle, administration route and schedule, dosing, detection of gene expression, and others. This review will primarily focus on optimization of the delivery vehicle formulation. These formulation issues include morphology of the complexes, lipids used, flexibility versus rigidity, colloidal suspension, overall charge, serum stability, half-life in circulation, biodistribution, delivery to and dissemination throughout target tissues. Optimizing all components of the delivery system will allow broad use of liposomal complexes to treat or cure human diseases or disorders.


Hepatic metabolism of N-hydroxy-N-methyl-4-aminoazobenzene and other N-hydroxy arylamines to reactive sulfuric acid esters.
Hepatic cytosols catalyzed a 3'-phosphoadenosine 5'-phosphosulfate (PAPS)-dependent O-sulfonation of N-hydroxy-N-methyl-4-aminoazobenzene (N-HO-MAB) and of several other N-hydroxy arylamines. The presumed product from N-HO-MAB, N-methyl-4-aminoazobenzene-N-sulfate, reacted with added guanosine to yield N-(guanosin-8-yl)-N-methyl-4-aminoazobenzene, with methionine to form a sulfonium derivative that decomposed to yield 3-methylmercapto-N-methyl-4-aminoazobenzene, and with ribosomal RNA to give a bound derivative. N-Methyl-4-aminoazobenzene was converted to N-(guanosin-8-yl)-N-methyl-4-aminoazobenzene in concerted N-oxidation and O-sulfonation reactions conducted aerobically with a fortified 10,000 X g rat liver supernatant. In the absence of an added nucleophile, metabolically formed N-methyl-4-aminoazobenzene-N-sulfate (or the nitrenium ion from this unstable ester) was reduced by N-HO-MAB to form N-methyl-4-aminoazobenzene; the N-HO-MAB was oxidized, probably through a nitrone intermediate, to yield products that included N-hydroxy-4-aminoazobenzene and formaldehyde. An analogous reaction was noted between N-benzoyloxy-N-methyl-4-aminoazobenzene and N-HO-MAB in the absence of cytosol and PAPS. Hepatic N-HO-MAB sulfotransferase activities were in the order: male rat greater than female rat, male rabbit, male guinea pig, male mouse greater than male hamster. Male rat kidney and small intestine cytosols had low activities; the other tissues studied had little or no activity. Hepatic sulfotransferase activities for N-HO-MAB and N-hydroxy-N-acetyl-2-aminofluorene displayed different pH optima and inhibitor and activator responses. The rates of PAPS-dependent rat liver cytosol-catalyzed esterification of N-hydroxy-N-ethyl-4-aminoazobenzene, N-hydroxy-4-aminoazobenzene, and N-hydroxy-1- and 2-naphthylamine were 20 to 50% of that for N-HO-MAB. Activities for trans-N-hydroxy-4-aminostilbene, N-hydroxy-2-aminofluorene, N-hydroxyaniline, and N-hydroxy-N-methyl-N-benzylamine were not detected. No microsomal reduced nicotinamide adenine dinucleotide-dependent reduction or reduced nicotinamide adenine dinucleotide phosphate-dependent oxidation or cytosolic transferase reactions for N-HO-MAB, except the above-described PAPS-dependent reaction, were detected in rat liver.


Model of translational cancer research in multiple myeloma.
Recently, intensive laboratory and preclinical studies have identified and validated therapeutic molecular targets in multiple myeloma (MM). The introduction of novel agents such as the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide, which were rapidly translated from preclinical studies at the Dana-Farber Cancer Institute into clinical trials, has changed the treatment paradigm and markedly extended overall survival; MM has therefore become a remarkable example of translational cancer research in new drug development. In this article, with the aim of determining the key factors underlying success in translational research, we focus on our studies of MM at Dana-Farber Cancer Institute as well as at our institutes. The identification of these key factors will help to promote translational cancer research not only in MM but also in other hematologic malignancies and solid tumors, to develop novel therapies, to overcome drug resistance, and to thereby improve the prognosis of cancer patients.


Public hospital pathology--at what cost?
Public hospital laboratories have in the past fended off financial scrutiny and accountability on the grounds of their complexity and lack of compelling need. However, the cost of providing diagnostic laboratory services has now come under intense scrutiny because of budget reductions and options for private sector competition. Costing of pathology services is not difficult, but their organisation and outputs do have unique features that need to be understood and defined to ensure that the costing model used provides robust data that accurately reflects how resources are consumed. The cost data generated for diagnostic services can then be compared to the various benchmarks widely used for activity-based funding, such as the Commonwealth Medical Benefits Schedule and the pathology component of the AN-DRG Service Weights System, while the requirement and funding for other activities can be rationally determined.


Zika Virus Subgenomic Flavivirus RNA Generation Requires Cooperativity between Duplicated RNA Structures That Are Essential for Productive Infection in Human Cells.
Zika virus (ZIKV) is an emerging flavivirus, mainly transmitted by mosquitoes, which represents a global health threat. A common feature of flavivirus-infected cells is the accumulation of viral noncoding subgenomic RNAs by partial degradation of the viral genome, known as sfRNAs, involved in immune evasion and pathogenesis. Although great effort is being made to understand the mechanism by which these sfRNAs function during infection, the picture of how they work is still incomplete. In this study, we developed new genetic tools to dissect the functions of ZIKV RNA structures for viral replication and sfRNA production in mosquito and human hosts. ZIKV infections mostly accumulate two kinds of sfRNAs, sfRNA1 and sfRNA2, by stalling genome degradation upstream of duplicated stem loops (SLI and SLII) of the viral 3' untranslated region (UTR). Although the two SLs share conserved sequences and structures, different functions have been found for ZIKV replication in human and mosquito cells. While both SLs are enhancers for viral infection in human cells, they play opposite roles in the mosquito host. The dissection of determinants for sfRNA formation indicated a strong cooperativity between SLI and SLII, supporting a high-order organization of this region of the 3' UTR. Using recombinant ZIKV with different SLI and SLII arrangements, which produce different types of sfRNAs or lack the ability to generate these molecules, revealed that at least one sfRNA was necessary for efficient infection and transmission in Aedes aegypti mosquitoes. Importantly, we demonstrate an absolute requirement of sfRNAs for ZIKV propagation in human cells. In this regard, viruses lacking sfRNAs, constructed by deletion of the region containing SLI and SLII, were able to infect human cells but the infection was rapidly cleared by antiviral responses. Our findings are unique for ZIKV, since in previous studies, other flaviviruses with deletions of analogous regions of the genome, including dengue and West Nile viruses, accumulated distinct species of sfRNAs and were infectious in human cells. We conclude that flaviviruses share common strategies for sfRNA generation, but they have evolved mechanisms to produce different kinds of these RNAs to accomplish virus-specific functions.IMPORTANCE Flaviviruses are important emerging and reemerging human pathogens. Understanding the molecular mechanisms for viral replication and evasion of host antiviral responses is relevant to development of control strategies. Flavivirus infections produce viral noncoding RNAs, known as sfRNAs, involved in viral replication and pathogenesis. In this study, we dissected molecular determinants for Zika virus sfRNA generation in the two natural hosts, human cells and mosquitoes. We found that two RNA structures of the viral 3' UTR operate in a cooperative manner to produce two species of sfRNAs and that the deletion of these elements has a profoundly different impact on viral replication in the two hosts. Generation of at least one sfRNA was necessary for efficient Zika virus infection of Aedes aegypti mosquitoes. Moreover, recombinant viruses with different 3' UTR arrangements revealed an essential role of sfRNAs for productive infection in human cells. In summary, we define molecular requirements for Zika virus sfRNA accumulation and provide new ideas of how flavivirus RNA structures have evolved to succeed in different hosts.


Tracheotomy Outcomes in 64 Ventilated COVID-19 Patients at a High-Volume Center in Bronx, NY.
The COVID-19 pandemic has resulted in a dramatic increase in the number of patients requiring prolonged mechanical ventilation. Few studies have reported COVID-19 specific tracheotomy outcomes, and the optimal timing and patient selection criteria for tracheotomy remains undetermined. We delineate our outcomes for tracheotomies performed on COVID-19 patients during the peak of the pandemic at a major epicenter in the United States. This is a retrospective observational cohort study. Mortality, ventilation liberation rate, complication rate, and decannulation rate were analyzed. Sixty-four patients with COVID-19 underwent tracheotomy between April 1, 2020 and May 19, 2020 at two tertiary care hospitals in Bronx, New York. The average duration of intubation prior to tracheotomy was 20 days ((interquartile range [IQR] 16.5-26.0). The mortality rate was 33% (n = 21), the ventilation liberation rate was 47% (n = 30), the decannulation rate was 28% (n = 18), and the complication rate was 19% (n = 12). Tracheotomies performed by Otolaryngology were associated with significantly improved survival (P < .05) with 60% of patients alive at the conclusion of the study compared to 9%, 12%, and 19% of patients undergoing tracheotomy performed by Critical Care, General Surgery, and Pulmonology, respectively. So far, this is the second largest study describing tracheotomy outcomes in COVID-19 patients in the United States. Our early outcomes demonstrate successful ventilation liberation and decannulation in COVID-19 patients. Further inquiry is necessary to determine the optimal timing and identification of patient risk factors predictive of improved survival in COVID-19 patients undergoing tracheotomy. 4-retrospective cohort study Laryngoscope, 131:E1797-E1804, 2021.


Evaluation of statistical treatments of left-censored environmental data using coincident uncensored data sets: I. Summary statistics.
The main classes of statistical treatment of below-detection limit (left-censored) environmental data for the determination of basic statistics that have been used in the literature are substitution methods, maximum likelihood, regression on order statistics (ROS), and nonparametric techniques. These treatments, along with using all instrument-generated data (even those below detection), were evaluated by examining data sets in which the true values of the censored data were known. It was found that for data sets with less than 70% censored data, the best technique overall for determination of summary statistics was the nonparametric Kaplan-Meier technique. ROS and the two substitution methods of assigning one-half the detection limit value to censored data or assigning a random number between zero and the detection limitto censored data were adequate alternatives. The use of these two substitution methods, however, requires a thorough understanding of how the laboratory censored the data. The technique of employing all instrument-generated data--including numbers below the detection limit--was found to be less adequate than the above techniques. At high degrees of censoring (greater than 70% censored data), no technique provided good estimates of summary statistics. Maximum likelihood techniques were found to be far inferior to all other treatments except substituting zero or the detection limit value to censored data.


Asthma therapy modulates priming-associated blood eosinophil responsiveness in allergic asthmatics.
Eosinophils play an important role in the pathogenesis of asthma. Several pro-inflammatory responses of eosinophils are primed in vivo in this disease. The aim of the present study was to investigate whether regular antiasthma treatment could modulate priming-sensitive cytotoxic mechanisms of human eosinophils. In a randomized, two-centre, double-blind parallel group study, the effect of 8 weeks of treatment with salmeterol xinafoate 50 microg b.i.d., beclomethasone dipropionate 400 microg b.i.d. or both on pulmonary function and the activation of priming-sensitive cytotoxic mechanisms of eosinophils, i.e. degranulation of eosinophil cationic protein (ECP) in serum, and activation of isolated eosinophils in the context of induction of the respiratory burst and release of platelet-activating factor (PAF) were tested. These effects were evaluated in 40 allergic asthmatics before and 24 h after allergen inhalation challenge. Whereas baseline forced expiratory volume in one second (FEV1) improved in all treatment groups, only treatment with a combination of salmeterol and beclomethasone significantly inhibited the allergen-induced increase in serum ECP, and (primed/unprimed) PAF-release, suggesting inhibition of eosinophil priming after allergen challenge. In contrast to the combination therapy, monotherapy with beclomethasone had no influence on allergen-induced PAF-release, suggesting an additional anti-inflammatory effect of salmeterol during combination therapy. Monotherapy with beclomethasone inhibited the prechallenge serum-treated zymosan (STZ) (0.1 mg mL(-1))-induced respiratory burst and the allergen-induced increase in serum ECP levels, reflecting pre- and postchallenge anti-inflammatory effects. During monotherapy with salmeterol, an allergen-induced increase in serum ECP concentration and STZ (0.1 mg x mL(-1))-induced respiratory burst was observed, suggesting that treatment with salmeterol alone had no effect on priming-sensitive eosinophil cytotoxic mechanisms. In conclusion, this study shows that standard asthma therapy leads to inhibition of eosinophil priming of cytotoxic mechanisms in vivo.


Relevance of Campylobacter to public health--the need for a One Health approach.
Campylobacter species belong to the most important foodborne bacteria which cause gastroenteritis in humans in both developed and developing countries. With increasing reporting rates, the public awareness towards Campylobacter infections is growing continuously. This strengthens the necessity to establish intervention measures for prevention and control of thermophilic Campylobacter spp. along the food chain, as in particular poultry and poultry meat represent a major source of human infections. An interdisciplinary One Health approach and a combined effort of all stakeholders are necessary to ultimately reduce the burden of campylobacteriosis cases in humans. Numerous studies point out, however, that at present a complete elimination of Campylobacter in the food chain is not feasible. The present aim should therefore be to establish control measures and intervention strategies to minimize the occurrence of Campylobacter spp. in livestock (e.g. poultry flocks) and to reduce the quantitative Campylobacter burden in animals and foods. To this end, a combination of intervention methods at different stages of the food chain appears most promising. That has to be accompanied by targeted consumer advice and education campaigns to raise the awareness towards Campylobacter infections.


A High-Content Screen for the Identification of Plant Extracts with Insulin Secretion-Modulating Activity.
Bioactive plant compounds and extracts are of special interest for the development of pharmaceuticals. Here, we describe the screening of more than 1100 aqueous plant extracts and synthetic reference compounds for their ability to stimulate or inhibit insulin secretion. To quantify insulin secretion in living MIN6 β cells, an insulin-Gaussia luciferase (Ins-GLuc) biosensor was used. Positive hits included extracts from Quillaja saponaria, Anagallis arvensis, Sapindus mukorossi, Gleditsia sinensis and Albizia julibrissin, which were identified as insulin secretion stimulators, whereas extracts of Acacia catechu, Myrtus communis, Actaea spicata L., Vaccinium vitis-idaea and Calendula officinalis were found to exhibit insulin secretion inhibitory properties. Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) were used to characterize several bioactive compounds in the selected plant extracts, and these bioactives were retested for their insulin-modulating properties. Overall, we identified several plant extracts and some of their bioactive compounds that may be used to manipulate pancreatic insulin secretion.


A Prospective Evaluation of Shared Decision-making Regarding Analgesics Selection for Older Emergency Department Patients With Acute Musculoskeletal Pain.
Musculoskeletal pain is a common reason for emergency department (ED) visit by older adults. Outpatient pain management following ED visits in this population is challenging as a result of contraindications to, and side effects from, available therapies. Shared decision-making (SDM) between patients and emergency physicians may improve patient experiences and health outcomes. Among older ED patients with acute musculoskeletal pain, we sought to characterize their desire for involvement in the selection of outpatient analgesics. We also sought to assess the impact of SDM on change in pain at 1 week, patient satisfaction, and side effects. This was a prospective study of adults aged 60 years and older presenting to the ED with acute musculoskeletal pain. Participants' desire to contribute to outpatient analgesic selection was assessed by phone within 24 hours of ED discharge using the Control Preferences Scale and categorized as active, collaborative, or passive. The extent to which SDM occurred in the ED was also assessed within 24 hours of discharge using the 9-item Shared Decision Making Questionnaire, and scores were subsequently grouped into tertiles of low, middle, and high SDM. The primary outcome was change in pain severity between the ED visit and 1 week. Secondary outcomes included satisfaction regarding the decision about how to treat pain at home, satisfaction with the pain medication itself, and side effects. Desire of participants (N = 94) to contribute to the decision regarding selection of outpatient analgesics varied: 16% active (i.e., make the final decision themselves), 37% collaborative (i.e., share decision with provider), and 47% passive (i.e., let the doctor make the final decision). The percentage of patients who desired an active role in the decision was higher for patients who were college educated versus those who were not college educated (28% vs. 11%; difference 17%, 95% confidence interval [CI] = 0% to 35%), received care from a nurse practitioner versus a resident or an attending physician (32% vs. 9%; difference 23%, 95% CI = 4% to 42%), or received care from a female versus a male provider (24% vs. 5%; difference 19%, 95% = CI 5% to 32%). After potential confounders were adjusted for, the mean decrease in pain severity from the ED visit to 1-week follow-up was not significantly different across tertiles of SDM (p = 0.06). Higher SDM scores were associated with greater satisfaction with the discharge pain medications (p = 0.006). SDM was not associated with the class of analgesic received. In this sample of older adults with acute musculoskeletal pain, the reported desire of patients to contribute to decisions regarding analgesics varied based on both patient and provider characteristics. SDM was not significantly related to pain reduction in the first week or type of pain medication received, but was associated with greater patient satisfaction.


Modeling Human Digestive Diseases With CRISPR-Cas9-Modified Organoids.
Insights into the stem cell niche have allowed researchers to cultivate adult tissue stem cells as organoids that display structural and phenotypic features of healthy and diseased epithelial tissues. Organoids derived from patients' tissues are used as models of disease and to test drugs. CRISPR-Cas9 technology can be used to genetically engineer organoids for studies of monogenic diseases and cancer. We review the derivation of organoids from human gastrointestinal tissues and how CRISPR-Cas9 technology can be used to study these organoids. We discuss burgeoning technologies that are broadening our understanding of diseases of the digestive system.


Assessment of body composition in pediatric patients with cystic fibrosis.
Cystic fibrosis (CF) leads to pathological changes in organs that express the cystic fibrosis transmembrane conductance regulator (CFTR), including secretory cells of the digestive tract and the pancreas. Maintaining nutritional sufficiency is challenging for CF patients and therefore accurate monitoring is important for their clinical management. The objectives of this study were to evaluate the effectiveness of skinfold measurements as an accurate method for determining body composition (fat mass (FM) and lean body mass (LBM)) of this population, using dual-energy X-ray absorptiometry (DEXA) as a gold standard comparison and to determine the most accurate equation for this calculation in children with CF. Fifty-five pediatric patients with CF participated in the study. FM and LBM calculated via four methods: Slaughter, Durnin, Durenberg (2-site and 4-site). The relationship between the methods and DEXA results were estimated by intraclass-correlation coefficient (ICC) and Bland and Altman analyses. The Slaughter method was the most accurate (ICC of 0.92 for FM and 0.99 for LBM) and displayed the least bias over the range of FM and LBM in CF patients. In addition, the results of Bland Altman analyses comparing each skinfold method to DEXA, revealed that the results were evenly distributed along the range of values for the Slaughter calculation, whereas the other three methods under and over estimated % fat results at the upper and lower ends of the range respectively. We therefore conclude that the Slaughter method may be used for body composition assessment of pediatric CF patients. This provides clinical teams with a simple, accurate and non-invasive method that can be used to monitor nutritional status in pediatric patients with CF.


A new fluorometric method for measuring the action of C apolipoproteins on milk lipoprotein lipase.
Monolayer vesicles containing pyrene-labelled nonanoyltriglyceride (1-2 ditetradecyl 3-pyrene nonanoyl glyceride) were used as a substrate to measure bovine milk lipoprotein lipase activity. The activation of lipoprotein lipase by synthetic fragments of apolipoprotein C II and apo C III was measured. Fragments 30-78 and 43-78 had actions similar to that of the entire apo C II. Fragments 50-78 and 55-78 were 50% active, fragment 60-78 was 10% active and fragment 66-78 was inactive. Thus the activating capacity depended on the length of the carboxyterminal fragment. Replacing tyrosine 62 in apo C II by glycine removed all lipoprotein lipase activating capacity, while making Tyr 62 less accessible for binding to lipids and enzyme decreased apo C II activating capacity. Apo C III1 inhibited both basal lipoprotein lipase activity (no apo C II) and lipoprotein lipase activated by apo C II. Apo C III, fragment A (1-40) which did not bind lipids, had no inhibitory effect, while fragment B(41-79) had the same effect as whole apo C III,. Apo AI, AII and C I also inhibited lipoprotein lipase. The fluorometric assay is easy to perform, and suitable for metabolic studies such as fatty-acid exchanges between lipoproteins, as it produces no alteration in the reaction products. It also avoids the use of a radio-labelled substrate.


Life threat and posttraumatic stress in school-age children.
One hundred fifty-nine children (14.5% of the student body) were sampled after a fatal sniper attack on their elementary school playground. Systematic self-reports of posttraumatic stress disorder (PTSD) symptoms were obtained by use of a child PTSD Reaction Index. Analysis of variance revealed significant differences by exposure but not by sex, ethnicity, or age. Additional analyses were conducted of individual item response, overall severity of PTSD reaction, symptom grouping, and previous life events. The results provide strong evidence that acute PTSD symptoms occur in school-age children with a notable correlation between proximity to the violence and type and number of PTSD symptoms. Sampling at approximately one month after the trauma provided adequate delineation among exposure groups. The symptom profile of highly exposed children lends validity to the diagnosis of acute PTSD in childhood.


The surgical treatment of patients with osteosarcoma who sustain a pathologic fracture.
The presence of pathologic fracture in osteosarcoma raises concerns of tumor dissemination by the fracture hematoma and has been considered a contraindication to limb salvage surgery. Because this is a theoretical concern, there are little clinical data available in the literature on which to base treatment of these patients. Eighteen patients with osteosarcoma who sustained a pathologic fracture and had a minimum of 24 months of followup were reviewed retrospectively. Surgical treatment included nonoperative therapy, amputation, and limb salvage groups. Patients who refused surgical intervention (2) had a uniformly poor outcome. Patients who underwent amputation (6) had no local recurrences and 33% developed metastases. Patients who underwent limb salvage (10) experienced 3 local recurrences and 6 distant recurrences. Although the distant recurrence rate for patients undergoing amputation was no different from the rate for those undergoing limb salvage, the difference in local tumor control approached statistical significance. All patients who developed local recurrence died. Surgical treatment needs to be individualized and based on factors such as fracture displacement, stability, radiographic and histologic response to chemotherapy, and the perceived ability to resect the fracture hematoma completely.


Modulation of testicular androgen production in adolescent African catfish (Clarias gariepinus).
At 6 months of age the first spermatozoa appear in the testes of the African catfish considered to be adolescent, since the development to adulthood (12 months of age) is accompanied by further morphological and functional differentiation of Leydig cells. There are increasing plasma levels of 11-ketotestosterone (11-KT) and an increasing responsiveness to luteinizing hormone (LH) of testicular androgen secretion in vitro. Whether treatment of adolescent males with key hormones of the brain-pituitary-gonad axis [gonadotropin-releasing hormone (GnRH), LH, and 11-KT] affects the testicular steroidogenic response to a challenge with LH in vitro 7 days later has been investigated. Injection of GnRH (2.5 microg chicken GnRH-II per kilogram of body weight), LH (25 microg/kg), or a high dose of 11-KT (50 microg/kg) down-regulated basal and LH-stimulated testicular androgen secretion to a minimum of 35% of control values. Treatment with LH was, moreover, associated with changes in the ultrastructure of Leydig cell mitochondria which were either swollen and had a less electron-dense matrix or showed an elongated shape. Conversely, a moderate dose of 11-KT (20 microg/kg) enhanced LH-stimulated, but not basal, androgen secretion in vitro to a maximum of 190% of control values. In view of the generally low LH plasma levels and of the steadily increasing 11-KT plasma levels during puberty, 11-KT may be involved in the up-regulation of the testicular steroidogenic capacity observed during development to full maturity.


L-myc restriction fragment length polymorphism in Japanese patients with esophageal cancer.
L-myc polymorphism is a representative genetic trait related to an individual's susceptibility to several cancers. However, there have been no reports concerning the association between esophageal cancer and L-myc polymorphism. To analyze the distribution of polymorphism in Japanese patients with esophageal cancer, a molecular genotyping method using a polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was used. Based on an analysis of 65 Japanese patients with esophageal cancer and 107 healthy control subjects, a significant difference was observed in either the distribution of genotypes (P=0.012) or of allele frequencies between the two groups (P=0.004). The relative risk of esophageal cancer for genotypes including the shorter allele was 2.9 compared to the longer allele homozygote. Furthermore, the patients with S-allele had a tendency for poor prognosis among those with three genotypes. A significant difference between the distribution of genotypes and the incidence of lymph node metastasis was found based on the clinicopathological features of the cancers. These results suggest that L-myc polymorphism may be implicated as a genetic trait affecting an individual's susceptibility to esophageal cancer, at least among Japanese patients.


The evolution of viruses, the emergence of viral diseases: a synthesis that Martinus Beijerinck might enjoy.
The relentless production of viral variants and their selection for improved "fit" are seen from the perspective of the infectious disease sciences as ever-changing viral phenotypes and emerging disease risks. In the Darwinian cause:effect equation, we can characterize very well the effects of mutation and selection--these are catalogued as new viral phenotypes or pathotypes. However, the selective forces themselves driving such changes remain rather mysterious. Many selective forces must be at work, acting on the virus, the host, the host population and the environment. In some instances the virus seems to test new unoccupied niches in the absence of any apparent environmental change, but usually it is clear that changes are driven by human activity. Most important must be the ever increasing density of human, domestic animal and crop plant populations and the consequent increased opportunities for transmission of viral variants. Also important must be the great changes affecting all ecosystems--these especially favor the emergence of new zoonotic viruses and viral "species jumpers." The great increase in human travel and transport carries exotic viruses, vectors and hosts around the world, again favoring viral occupation of new niches. The rise of bioterrorism adds yet another threat. Increasing numbers of emerging viral disease episodes seem to be linked to a decline in global resources for proven public health programs, agricultural extension programs, and the like, programs that have stood in the way of the spread and evolution of viral pathogens. If the relationship between viral evolution and the emergence of new viral diseases is rooted firstly in the host and the host population, then more research and resources must be directed to intervention at these levels rather than at the level of the viruses themselves.


Enhancing the Mechanical and Tribological Properties of Cellulose Nanocomposites with Aluminum Nanoadditives.
Hydroxypropyl methylcellulose (HPMC) is a common hydrophilic and biodegradable polymer that can form films. This study incorporated aluminum nanoadditives as an enhancement reagent into a HPMC matrix. Mechanical properties of nanocompoistes, including the tensile strength and the elastic modulus, were analyzed with a nano-tensile tester. The incorporation of additives in HPMC films significantly enhances their mechanical and film barrier properties. Evidence of bonding between the additive and matrix was observed by Fourier-transform infrared spectrometer analysis. The additives occupy the spaces in the pores of the matrix, which increases the tendency of the pore to collapse and improves the chemical bonding between the base material and the additives. The incorporation of excess additives decreases the tensile strength due to ineffective collisions between the additives and the matrix. The wear test proves that the addition of nano-additives can improve the tribology performance of the HPMC composite while reducing the wear volume and the friction. Bonding between the nanoadditives and the matrix does not help release the nanoadditives into the wear interface as a third-body layer. The main reason to enhance the tribology performance is that the nanoadditives improve the load-capacity of the composite coating. This hybrid composite can be useful in many sustainability applications.


Classification of patients with cardiac amyloidosis using machine learning models on Italian electronic clinical health records.
Amyloidosis refers to a range of medical conditions in which misshapen proteins accumulate in various organs and tissues, forming insoluble fibrils. Cardiac amyloidosis is frequently linked to the buildup of misfolded transthyretin (TTR) or immunoglobulin light chains (AL). Delayed diagnosis, due to lack of disease awareness, results in a poor prognosis, especially in patients with AL amyloidosis. Early identification is therefore a key factor to improve patient outcomes. This study investigates the use of supervised machine-learning algorithms to support clinicians in classifying amyloidosis and control subjects. The aim of this work is to foster model interpretability reporting the most important risk factors in predicting the presence of cardiac amyloidosis. We analyzed electronic health records (EHRs) of 418 participants acquired in a time window of 12 years as part of a case-control study conducted in Fondazione Toscana Gabriele Monasterio (Italy) clinical practice. This work paves the way for the creation of digital health solutions that can aid in amyloidosis screening. The effective handling, analysis, and interpretation of these solutions can have a transformative effect on modern healthcare, offering new opportunities for improved patient care.