Cerebrospinal fluid substance P concentrations are elevated in patients with Alzheimer's disease.
The neuropeptides substance P, orexin A (hypocretin-1) and neurotensin are signaling molecules that influence brain activity. We examined their cerebrospinal fluid (CSF) levels in a study population consisting of Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n=32), stable MCI (SMCI, n=13), other dementias (n=15), and healthy controls (n=20). CSF substance P level was increased in AD patients compared to patients with other dementias and healthy controls (P<0.05 and P<0.01, respectively). Patients with other dementia or SMCI had lower CSF orexin A level than AD patients (both P<0.05) and marginally lower level than healthy controls (both P=0.05). CSF neurotensin level was similar in all groups. In the total study population (n=80), CSF substance P level correlated positively with CSF levels of T-tau and P-tau, and in AD patients (n=32), CSF substance P level correlated positively with CSF Aβ1-42 level. In conclusion, CSF substance P level was elevated in AD patients and correlated with CSF Aβ1-42 level, a well established marker of senile plaque pathology. The role of low CSF orexin A level in other dementias or SMCI needs to be explored in further studies.


Ginsenoside Rg1 activates ligand-independent estrogenic effects via rapid estrogen receptor signaling pathway.
Ginsenoside Rg1 was shown to exert ligand-independent activation of estrogen receptor (ER) via mitogen-activated protein kinase-mediated pathway. Our study aimed to delineate the mechanisms by which Rg1 activates the rapid ER signaling pathways. ER-positive human breast cancer MCF-7 cells and ER-negative human embryonic kidney HEK293 cells were treated with Rg1 (10-12M, 10-8M), 17ß-estradiol (10-8M), or vehicle. Immunoprecipitation was conducted to investigate the interactions between signaling protein and ER in MCF-7 cells. To determine the roles of these signaling proteins in the actions of Rg1, small interfering RNA or their inhibitors were applied. Rg1 rapidly induced ERα translocation to plasma membrane via caveolin-1 and the formation of signaling complex involving linker protein (Shc), insulin-like growth factor-I receptor, modulator of nongenomic activity of ER (MNAR), ERα, and cellular nonreceptor tyrosine kinase (c-Src) in MCF-7 cells. The induction of extracellular signal-regulated protein kinase and mitogen-activated protein kinase kinase (MEK) phosphorylation in MCF-7 cells by Rg1 was suppressed by cotreatment with small interfering RNA against these signaling proteins. The stimulatory effects of Rg1 on MEK phosphorylation in these cells were suppressed by both PP2 (Src kinase inhibitor) and AG1478 [epidermal growth factor receptor (EGFR) inhibitor]. In addition, Rg1-induced estrogenic activities, EGFR and MEK phosphorylation in MCF-7 cells were abolished by cotreatment with G15 (G protein-coupled estrogen receptor-1 antagonist). The increase in intracellular cyclic AMP accumulation, but not Ca mobilization, in MCF-7 cells by Rg1 could be abolished by G15. Ginsenoside Rg1 exerted estrogenic actions by rapidly inducing the formation of ER containing signalosome in MCF-7 cells. Additionally, Rg1 could activate EGFR and c-Src ER-independently and exert estrogenic effects via rapid activation of membrane-associated ER and G protein-coupled estrogen receptor.


Drought and changes in leaf orientation for two California chaparral shrubs: Ceanothus megacarpus and Ceanothus crassifolius.
Predawn xylem pressure potentials were measured on two California chaparral shrubs, Ceanothus megacarpus and Ceanothus crassifolius, throughout the winter and spring growing season and into the summer drought. On the days xylem pressure potentials were measured, leaf orientation measurements were made on a population of marked leaves from the same shrubs. Predawn xylem pressure potentials decreased from -0.1 MPa in both species to -7.8 and -6.6 MPa in C. megacarpus and C. crassifolius, respectively, between May and August, 1981. Leaf inclinations became more vertical during this period with the greatest change observed in C. crassifolius. This change in leaf inclination was reversible, and, in the late winter and early spring, one year old leaves became more horizontal. Leaf azimuths were random and did not change seasonally. Simulations of solar radiation interception indicated that the increase in leaf inclination associated with summer drought reduced the absorption of solar radiation in August by 6% for C. megacarpus and 20% for C. crassifolius. Standard leaf energy budget calculations suggest that steep leaf inclinations would result in slightly lower leaf temperatures and transpiration rates under summer conditions.


Systematic comparison of family history and polygenic risk across 24 common diseases.
Family history is the standard indirect measure of inherited susceptibility in clinical care, whereas polygenic risk scores (PRSs) have more recently demonstrated potential for more directly capturing genetic risk in many diseases. Few studies have systematically compared how these overlap and complement each other across common diseases. Within FinnGen (N = 306,418), we leverage family relationships, up to 50 years of nationwide registries, and genome-wide genotyping to examine the interplay of family history and genome-wide PRSs. We explore the dynamic for three types of family history across 24 common diseases: first- and second-degree family history and parental causes of death. Covering a large proportion of the burden of non-communicable diseases in adults, we show that family history and PRS are independent and not interchangeable measures, but instead provide complementary information on inherited disease susceptibility. The PRSs explained on average 10% of the effect of first-degree family history, and first-degree family history 3% of PRSs, and PRS effects were independent of both early- and late-onset family history. The PRS stratified the risk similarly in individuals with and without family history. In most diseases, including coronary artery disease, glaucoma, and type 2 diabetes, a positive family history with a high PRS was associated with a considerably elevated risk, whereas a low PRS compensated completely for the risk implied by positive family history. This study provides a catalogue of risk estimates for both family history of disease and PRSs and highlights opportunities for a more comprehensive way of assessing inherited disease risk across common diseases.


Reaching new heights: insights into the genetics of human stature.
Human height is a highly heritable, classic polygenic trait. Until recently, there had been limited success in identifying the specific genetic variants that explain normal variation of human height. The advent of large-scale genome-wide association studies, however, has led to dramatic progress. In the past 18 months, the first robust common variant associations were identified and there are now 44 loci known to influence normal variation of height. In this review, we summarize this exciting recent progress, discuss implicated biological pathways, the overlap with monogenic growth and skeletal dysplasia syndromes, links to disease and insights into the genetic architecture of this model polygenic trait. We also discuss the strong probability of finding several hundred more such loci in the near future.


A novel surfactant protein C L55F mutation associated with interstitial lung disease alters subcellular localization of proSP-C in A549 cells.
Heterozygous mutations of SFTPC, the gene-encoding surfactant protein C (SP-C), result in interstitial lung disease (ILD). However, characterization of mutations located in the mature domain of precursor SP-C (proSP-C) is limited. This study examined the molecular pathogenesis of such a mutation of ILD. We employed sequencing of SFTPC and established A549 cells stably expressing several proSP-C mutants. Histopathology and transmission electron microscopy (TEM) of lung tissue from a pediatric patient with ILD were assessed. Effects of mutant proSP-C were evaluated by western blotting, immunofluorescence, and TEM. Sequencing of SFTPC revealed a novel heterozygous mutation, c.163C>T (L55F). In lung tissue, abnormal localization of proSP-C was observed by immunohistochemistry, and small and dense lamellar bodies (LBs) in type II alveolar epithelial cells (AECs) were detected by TEM. TEM of A549 cells stably expressing proSP-C(L55F) displayed abnormal cytoplasmic organelles. ProSP-C(L55F) exhibited a band pattern similar to that of proSP-C(WT) for processed intermediates. Immunofluorescence studies demonstrated that proSP-C(L55F) partially colocalized in CD63-positive cytoplasmic vesicles of A549 cells, which was in contrast to proSP-C(WT). We detected a novel c.163C>T mutation located in the mature domain of SFTPC associated with ILD that altered the subcellular localization of proSP-C in A549 cells.


Preoperative hypoalbuminemia is an independent predictor of poor perioperative outcomes in women undergoing open surgery for gynecologic malignancies.
To quantify the impact of preoperative hypoalbuminemia on 30-day mortality and morbidity after gynecologic cancer surgery. Patients included in the National Surgical Quality Improvement Program (NSQIP) dataset who underwent any non-emergent surgery for gynecologic malignancy between 1/1/2008 and 12/31/2010 were identified. Analysis was conducted with albumin both as a dichotomous variable (<3.5 g/dl was defined as low albumin) and as a continuous variable to determine a clinically relevant cut-off value. Of the total 3171 patients identified, 2110 had preoperative albumin levels available for analysis. In addition, 279 (13.3%) of these patients had low albumin levels. According to multivariate analysis, the low albumin group had significantly higher odds of developing one or more post-operative complications (OR-2,CI: 1.47-2.73, p<0.0001), three or more complications (OR-4.1,CI: 2.31-7.1, p<0.0001), surgical complications (OR-2.39,CI: 1.59-3.58, p<0.0001), thromboembolic complications (OR-2.59,CI: 1.33-5.06, p<0.0001), pulmonary complications (OR-4.06,CI: 2.05-8.03, p<0.0001), or infectious complications (OR-1.84,CI: 1.26-2.69, p<0.0001) and a higher 30-day mortality (OR-6.52,CI: 2.51-16.95, p<0.0001). Upon subgroup analysis, this difference was not found in patients undergoing laparoscopic surgery. In patients undergoing open surgery, the probability of experiencing one or more post-operative complications increased linearly with the decrease in albumin level; however, the probability of patients experiencing three or more complications and 30-day mortality increased sharply as soon as the albumin level decreased below 3g/dl. Preoperative albumin levels <3g/dL identify a population of patients at a very high-risk of experiencing perioperative morbidity and 30-day mortality after open surgery.


A clinical trial of topically applied 3 percent vidarabine against recurrent herpes labialis.
Seventy-six participants were enrolled in a clinical trial to determine therapeutic effectiveness of 3 percent vidarabine applied topically to recurrent perioral herpetic lesions. Following a 6- to- 12-month natural history phase, a 12-month clinical trial was conducted. Seventy participants developed 463 lesions during 361 episodes. Three percent vidarabine in a water-miscible gel was applied six times daily for 7 days to each lesion in the experimental group. Identically packaged placebo was used by the control group. Group assignment was by computer-generated randomization. Lesion size was reduced when vidarabine, rather than placebo, was applied. The difference was statistically significant (Student's t test, P = 0.02). Vesiculation followed tingling more rapidly when vidarabine, rather than placebo, was applied prior to vesiculation (P = 0.05). No significant difference between the two groups was found in episode frequency or lesion duration. Adverse reactions to vidarabine were not experienced.


Hyperosmolar diabetic ketoacidosis-- review of literature and the shifting paradigm in evaluation and management.
Hyperosmolar diabetic ketoacidosis (H-DKA), a distinct clinical entity, is the overlap of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). We describe the clinical presentation, metabolic aberrations, and associated morbidity/mortality of these cases with H-DKA. We highlight the problem areas of medical care which require particular attention when caring for pediatric diabetes patients presenting with H-DKA. In our study we reviewed the literature back to 1963 and retrieved twenty-four cases meeting the criteria of H-DKA: glucose >600 mg/dL, pH < 7.3, bicarbonate <15 mEq/L, and serum osmolality >320 mOsm/kg, while adding three cases from our institution. Average age of presentation of H-DKA was 10.2 years ± 4.5 years in females and 13.3 years ± 4 years in males, HbA1c was 13%. Biochemical parameters were consistent with severe dehydration: serum osmolality = 394.8±55 mOsm/kg, BUN = 48±22 mg/dL, creatinine = 2.81±1.03 mg/dL. Acute kidney injury, present in 12 cases, was the most frequent end-organ complication. Multi-organ involvement with AKI, rhabdomyolysis, pancreatitis, neurological and cardiac issues such as arrhythmias, are common in H-DKA. Aggressive fluid management, insulin therapy and supportive care can prevent acute and long term adverse outcomes in children and adolescents.


Entomological surveillance to assess potential outbreak of Aedes-borne arboviruses and insecticide resistance status of Aedes aegypti from Cape Coast, Ghana.
This study was conducted in Cape Coast, a major tourist destination in Ghana to assess the risk of an outbreak of Aedes-borne arboviruses based on entomological indicators and determine their susceptibility to pyrethroid insecticides. A larval survey was conducted in 414 houses between April and July 2017. Larvae collected were reared to adult for WHO susceptibility bioassay against four pyrethroid insecticides (Deltamethrin 0.05%, Permethrin 0.75%, Cyfluthrin 0.15%, Etofenprox 0.5%) and three different brands of mosquito coil; Heaven® (Dimefluthrin 0.03%), Sasso® (Esbiothrin 0.25%), and Fastkit® (D-allethrin 0.25%) as well as four enzyme-activities and F1534C kdr-mutation. Some physicochemical parameters were also measured in Aedes breeding sites. Three larval indices and water quality index (WQI) were calculated. The estimated larval indices were: House index - 68%, Container index - 44%, and Breteau index - 2.4. The level of resistance of the vector to the different pyrethroid insecticides and mosquito coils varied. F1534C kdr-mutation with an allele frequency of 35% and metabolic detoxifying enzyme activities are suspected to be the cause of resistance. Ae. aegypti breeding sites were found to contain organic and other anthropogenic pollutants. Based on the larval indices estimated, the population density of Ae. aegypti in Cape Coast was found to be sufficient to promote an outbreak of arboviruses. Pyrethroid resistance in the vector population could compromise the effectiveness of pyrethroid-based control strategies as was seen with the reduced efficacy of mosquito coils. With large number of international travellers to the city, there is a need to put in place a regular Aedes surveillance program for early response to any potential outbreaks.


Expression patterns of aristaless in developing appendages of Gryllus bimaculatus (cricket).
We report the isolation and expression patterns of aristaless (al), a paired-type homeobox gene, of Gryllus bimaculatus (Gb), a hemimetabola model insect. Gryllus al (Gbal) is expressed in the most distal region of developing labrum, antenna, mandible, maxilla, labium, leg, cercus, and hindgut. Gbal is also expressed in the proximal region, corresponding to the presumptive coxopodite, of the developing antenna, mandible, maxilla, labium, and leg, but not in the developing labrum, cercus, and hindgut. During development of the leg, expression of Gbal changes dynamically with the progress in leg segmentation: Gbal is expressed in order in the presumptive pretarsus, coxa, femur, tibia and tarsus before appearance of morphological segmentation.


Synthesis of 6-cinnamoyl-2H-benzo[b][1,4]oxazin-3(4H)-ones and their effects on A549 lung cancer cell growth.
A series of novel 6-cinnamoyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives was synthesized. The structures of compounds were characterized by (1)H NMR, IR, and MS. Moreover, representative crystal structure was determined by X-ray diffraction analysis. The preliminary biological evaluation of all these compounds showed that compounds 3a-3d would suppress the growth of A549 lung cells effectively by inducing autophagy and cell cycle arrest.


Evaluating the effects of wearing contact lenses: morning and afternoon testing.
Corneal steepening and myopic increases are characteristic of diurnal variations which affect habitual wearers of contact lenses. Testing before insertion of lenses and after wearing lenses for 8 hours provided a good indication of the magnitude of diurnal changes in 35 individuals.


Nurse perceptions of the quality of patient care: Confirming the importance of empowerment and job satisfaction.
This aim of this study was to investigate the interactive effects of psychological empowerment and job satisfaction on the relationship between high-performance work systems (HPWS) and nurses' perceptions of the quality of patient care they provide. Studies of high-performing organizations in a variety of industries have consistently reported a positive relationship between HPWS and performance outcomes. Although many of these studies have been conducted in manufacturing, similar findings of a positive correlation between aspects of HPWS and improved patient outcomes have been reported in international health care studies. We used regression analysis with tests of mediation and moderation to analyze survey responses collected in March 2008 of 201 nurses in a large regional Australian health service. Psychological empowerment fully mediated the relationship between HPWS and perceptions of quality of patient care. Job satisfaction moderated the relationship between HPWS and perceptions of quality of patient care. Hospital managers should focus on promoting HPWS and ensuring that nurse unit managers have the competencies to empower and to enhance the job satisfaction of their staff.


Quantification of thalamic nuclei in patients diagnosed with temporal lobe epilepsy and hippocampal sclerosis.
The aim of this study is to investigate the changes in the volume of individual thalamic nuclei in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS). We enrolled 80 TLE patients with HS and 40 healthy controls. All of the subjects underwent 3D T1-weighted imaging. The hippocampus subfields and thalamic nuclei were segmented using the FreeSurfer program. We investigated volume changes in thalamic nuclei according to the HS side involved, and types or antiepileptic drug (AED) response compared with healthy controls. Compared with healthy controls, patients with HS showed atrophy of thalamic nuclei involving right and left parafascicular nuclei. In the right HS, the atrophy of the right thalamic nucleus was more prominent than that of the left thalamic nucleus, whereas the reduction in the volume of left thalamic nuclei was more prominent in patients with left HS. The reduction in thalamic nuclear volumes was more prominent in HS type 1 (atrophy of both CA1 and CA4 regions) than in other HS types. The suprageniculate nuclear volumes were significantly increased in patients with drug-controlled epilepsy. Our study demonstrates thalamic nuclear atrophy in TLE patients with HS. In addition, the atrophy of individual thalamic nuclei varied according to the HS side, the HS types, and the AED response. These findings suggest that the role of thalamic nuclei varied in TLE with HS subtypes and displayed varying degrees of vulnerability in the pathology networks associated with the hippocampus.


Unintended consequences of health care legislation.
Unintended consequences of health care legislation threaten the financial and social well-being of the United States. Examples of major legislation resulting in unintended and unforeseen consequences include the Social Security Amendments Acts of 1989 and 1993 (the Stark laws), the Balanced Budget Act of 1997, and the Social Security Amendments Act of 1965 (Medicare and Medicaid). Each of these has had unintended financial and social outcomes. Spending for Medicare and Medicaid now equals an unsustainable 23% of the federal budget. Major reasons for unintended consequences include failure to appreciate the complexity of the issues, the open-ended nature of medical advances with attendant increases in costs, the inducement of change in behaviors in response to legislation, and the moral hazard of people spending other people's money. Actions that should be considered to avoid unintended consequences include more involvement of health professionals in the design of legislation, the inclusion of triggers to target review of legislatively defined programs, and the setting of time limits for sun-setting legislation. The ACR has played an important advocacy role and should continue to offer input to legislators, federal policymakers, and other stakeholders. Many opportunities exist to address the current financial situation by reducing the amount of unnecessary care delivered. Both major US political parties need to find the political will to compromise to chart the way forward. Some level of sacrifice is likely to be necessary from patients and providers and other stakeholders.


A twist in the tale of lipolytic enzymes.
Structural studies of phospholipase A2 in the presence of micelles, and investigations into molecular properties of lipids indicate that the mechanism of interfacial activation of lipolytic enzymes may be far more complex than presently supposed at present.


Antiracist symptom science: A call to action and path forward.
Nurse scientists recognize the experience of racism as a driving force behind health. However, symptom science, a pillar of nursing, has rarely considered contributions of racism. Our objective is to describe findings within symptom science research related to racial disparities and/or experiences of racism and to promote antiracist symptom science within nursing research. In this manuscript, we use an antiracist lens to review a predominant symptom science theory and literature in three areas of symptom science research-oncology, mental health, and perinatal health. Finally, we make recommendations for increasing antiracist research in symptom science by altering (a) research questions, (b) recruitment methods, (c) study design, (d) data analysis, and (e) dissemination of findings. Traditionally, symptom science focuses on individual level factors rather than broader contexts driving symptom experience and management. We urge symptom science researchers to embrace antiracism by designing research with the specific intent of dismantling racism at multiple levels.


Impact of various pressures on fracture resistance and microleakage of amalgam and composite restorations.
Pressure changes can influence dental restorations especially among divers. The aim of the current study was to evaluate the fracture resistance and microleakage of mesio-occluso-distal (MOD) amalgam and composite restorations undergoing pressure changes via diving and aviation simulation. For the fracture resistance test, 60 sound maxillary premolar teeth were randomly allocated to two groups. Each group was then divided into three subgroups (n = 10) for simulating scuba-diving (pressure cycle to 203 kPa, 2 bar), flight (50.6 kPa, 0.5 bar), and control (atmospheric pressure). The teeth underwent pressure cycles for one month and then the fracture resistance test was conducted on them using the Instron testing machine. Microleakage scores were afterwards recorded by using a 2% methylene blue dye for 24 hours. Composite restorations showed significantly higher fracture resistance values compared to the amalgam group (P < 0.05). The control group had significantly higher fracture resistance values compared to the dive group, whereas there was no significant difference between the control group and the flight group (P = 0.083). No significant difference in the level of microleakage was observed between restoration materials or pressure cycles (P > 0.05). Composite restorations showed better fracture resistance compared to the amalgam group. However, diving pressure cycles demonstrated adverse effects on the fracture resistance values of both restorative materials.


Diabetes and related metabolic risk factors among Arab Americans.
To estimate the incidence of noninsulin-dependent diabetes mellitus (NIDDM) and associated metabolic abnormalities such as impaired glucose tolerance, increased blood pressure, hyperinsulinemia, and obesity in the Arab-American community in the Detroit metropolitan area. Subjects were selected randomly from a computer-generated list provided by the Arab-American Center for Economic and Social Services. Laboratory studies included a 2-hour, 75-g oral glucose tolerance test with glucose, insulin, and C-peptide determinations. Of the 105 volunteers studied, 57 were women and 48 were men. Mean +/- SD age was 46.0 +/- 13.0 years. Body mass index was 30.4 +/- 6.8 kg/m2, with 68% of subjects having a body mass index of 27 kg/m2 or more. Of the study participants, 33% had NIDDM, 8.6% had impaired glucose tolerance, and 58% had normal glucose tolerance. Subjects with diabetes, compared with subjects who had normal glucose tolerance, exhibited increased fasting insulin (98 +/- 69 vs 55 +/- 31 pmol/L; p = 0.00056); higher cholesterol (6.03 +/- 1.03 vs 5.09 +/- 1.22 mmol/L; p = 0.00073); marginally lower high-density lipoprotein cholesterol (0.98 +/- 0.21 vs 1.14 +/- 0.31 mmol/L; p = 0.054); higher triglycerides (7.84 +/- 5.79 vs 3.83 +/- 2.15 mmol/L; p = 0.00002); and higher diastolic (83.7 +/- 8.9 vs 78.3 +/- 8.0 mm Hg; p = 0.014) as well as systolic (132.5 +/- 16.0 vs 119.0 +/- 10.6 mm Hg; p = 0.00001) blood pressures This pilot study demonstrates that diabetes may be a frequent medical problem in the Arab-American community. A well-designed epidemiologic study is warranted to validate these results and to elucidate the underlying mechanisms responsible for these findings.


Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment.
Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane potential and IFN-γ production. Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.


[Current legal framework conditions for running and utilization of biobanks : part 1: legal principles].
Research biomaterial banks (biobanks) are institutions which collect and prepare samples of human bodily substances (e.g. cells, tissues, body fluids and isolates from them), store personal, health and problem-related data of donors, collate samples and data and make them available in a suitable form for research purposes. The valid legal norms for the utilization and running of biobanks are complex and sometimes necessitate an assessment by the legal guardian.


An iterative process of global quality improvement: the International Standards for a Safe Practice of Anesthesia 2010.
To enhance patient safety through contemporaneous and comprehensive standards for a safe practice of anesthesia that augment, enhance, and support similar standards already published by various countries and that provide a resource for countries that have yet to formulate such standards. The Safe Anesthesia Working Group of the World Health Organization's "Safe Surgery Saves Lives" global initiative updated the 1992 International Standards for the Safe Practice of Anaesthesia (Standards) through an iterative process of literature review, consultation, debate, drafting, and refinement. These Standards address, in detail, the organization, support, practices, and infrastructure for anesthesia care. The Standards are grounded in the fundamental principle of safety in anesthesia, i.e., the continuous presence of an appropriately trained, vigilant anesthesia professional. In effect, the use of pulse oximetry during anesthesia is now considered mandatory, with acknowledgement that compromise may be unavoidable in emergencies. At the World Congress of Anaesthesiologists in 2008, drafts were presented for comment, further refinements were made, and the Revised Standards were adopted by the World Federation of Societies of Anaesthesiologists (WFSA). These Revised Standards were posted on the WFSA website for further feedback, and minor revisions followed. The International Standards for a Safe Practice of Anesthesia 2010 were endorsed by the Executive Committee of the WFSA in March 2010. Ongoing periodic revision is planned. While they are universally applicable, the 2010 Standards primarily target lesser-resourced areas. They are designed particularly for regions that have yet to formulate or adopt their own standards so as to promote optimum patient outcomes in every anesthetizing location in the world.


[Neonatal oxygen therapy. Monitoring of PO2 by using capillary microsample].
Capillary blood obtained from puncture of a warmed heel was tested for PO2 monitoring in management of 31 infants (1215-3920 g) with perinatal asphyxia and/or RDS. PO2 means during O2 administration were referred to mean values +/- I sigma for 108 normal term infants. All infants survived, with only a neurological complication due to a severe RDS with pneumothorax during CPAP treatment. We confirm the reliability of capillary microsampling collected blood for PO2 monitoring in RDS management too.


Sudden death due to Waterhouse-Friderichsen syndrome and purulent leptomeningitis caused by Acinetobacter calcoaceticus (Mima polymorpha).
A case of Waterhouse-Friderichsen syndrome presenting with purulent leptomeningitis causing sudden death is described. The causative agent, Acinetobacter calcoaceticus (Mina polymorpha), was determined by post-mortem microbiological examination.


Development of Data-Driven Triage Systems for Identifying Mortally Wounded Casualties-Implications for Future Large-Scale Combat Operations.
Uncontested air movement and advances for medical care of combat casualties have resulted in a decreased case fatality rate. However, in future large-scale combat operations, the military has established a plan for multidomain operations to defeat near-peer adversaries. Prolonged casualty care and mass casualty scenarios will become more prevalent. Prehospital friendly scoring systems such as the shock index (SI) and revised trauma score (RTS) may provide useful triage data. Development of accurate, data-driven, triage systems will be key to optimize management of resources, care, and transport of combat casualties. We included data from the Department of Defense Trauma Registry between 01 January 2007 to 17 March 2020. Data comprised of adult US military or coalition service members for analysis as the baseline cohort, and those who died within 24 hours were included in the early death cohort. We performed statistical analysis on demographics and injury data, SI and RTS to measure the receiver operating characteristics (ROC) of each value to predict early death. The early death cohort had a significantly higher injury severity score (25 vs. 5) and a higher percentage of serious injuries in every body region than the baseline cohort. The early death cohort sustained serious injuries to the head and neck at a rate five times that of the baseline cohort (43.4% vs 8.1%) with odds ratio (OR) of death 8.0 (95% confidence interval 5.7-11.1) followed by skin (13.6% versus 1.9%) with an OR of 6.3 (95% CI 3.8-10.3). The mean SI was 1.21 versus 0.80. The revised trauma score (RTS) was 4.18 versus 7.34. The RTS had a higher area under the receiver operating characteristic (0.896 versus 0.716 for SI). Serious injuries to the head and skin were most strongly associated with death within the first 24 hours. The RTS appears to be a more accurate tool than SI alone for assessing injury mortality. Military medical personnel should consider these factors when triaging casualties during future conflicts in resource limited settings with delayed evacuation.


Fatigue and psychological disorders in chronic hepatitis C.
Most patients with chronic hepatitis C report that they suffer from fatigue. The aim of this study was to determine if the symptom of fatigue can be a guide to indicate disease activity in chronic hepatitis C, or if it is related to psychological factors. 115 chronic hepatitis C patients attending a liver clinic at Wollongong Hospital, Wollongong, Australia, were asked to fill out a questionnaire on the functional impact of their fatigue, and a questionnaire on psychological parameters. These were correlated with a history of intravenous drug use, alcohol history, transaminase levels and liver biopsy findings. Fatigue weakly correlated with the level of fibrosis on the liver biopsy, but strongly correlated with all the psychological domains of depression, anxiety, somatization, interpersonal sensitivity and hostility. The level of fatigue strongly correlated with all the psychological domains, particularly depression, and not with our measures of disease activity.


Endoscopic myringoplasty: comparison of double layer cartilage-perichondrium graft and single fascia grafting.
To compare surgical results of endoscopic myringoplasty using double layer cartilage-perichondrium grafts versus single fascia grafts. Prospective, randomized, controlled. University-affiliated teaching hospital. In total,134 patients who underwent endoscopic myringoplasty were included in this study. Patients in group A received a double layer tragal cartilage-perichondrium graft and those in group B received a temporal muscle fascia graft. The groups were compared with respect to the pre- and postoperative air-bone gap (ABG) and the graft success rate. The graft success rate was 98.5% (66/67) in the Group A and 94.0% (63/67) in the Group B at 6 months, the difference wasn't statistically significant (p = 0.362). However, the graft success rate was 97.0% (65/67) in the Group A and 85.1% (57/67) in the Group B at 12 months, the difference was statistically significant (p = 0.034). In addition, only one patient (1.49%) had small keratin pearls in the Group A, no patients developed cholesteatoma of middle ear in either group. The endoscopic double layer perichondrium-cartilage graft technique is feasible for repairing medium or larger perforations, it has a better long-term graft success rate and less operative time compared with the single layer fascia graft technique. However, long-term hearing outcomes were the same for the single and double layer closure techniques.


Effects of marital status on survival of medullary thyroid cancer stratified by age.
Marital status has emerged as an important influence on several cancer outcomes, but its role in medullary thyroid cancer (MTC) remains unclear. This study was to explore the effects of marital status on the prognosis of MTC patients and to determine whether its effects vary by age. We retrospectively extracted 1344 eligible patients diagnosed with MTC between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Based on the marital status, we divided those patients into married and unmarried groups. We compared the difference in overall survival (OS) and cancer-specific survival (CSS) between married and unmarried via the Kaplan-Meier analysis. Univariate and multivariate Cox proportional models were performed to identify the prognostic factors of OS and CSS. There were 1344 MTC eligible patients in a total of which 883 (65.7%) were married and 461 (34.3%) were unmarried. The comparison observed between married and unmarried patients was as follows: male (45.2% vs. 28.0%), age (≥52 years) (55.9% vs. 44.6%), White (86.7% vs. 78.7%), and undergo surgery (97.7% vs. 93.3%). Multivariate analysis revealed unmarried status as a risk factor independently associated with worse OS (HR: 2.15, 95% CI: 1.59-2.92) rate and CSS (HR: 1.70, 95% CI: 1.17-2.47) rate. In a further analysis stratified by age, there was no significant difference in OS and CSS between married and unmarried patients younger than 52 years. For the remaining group with 52 years old and higher, unmarried patients showed significantly higher risk of OS and CSS than married patients at all stages of the pathology except M1 stage. Married patients with MTC have a better prognosis than unmarried ones. Age can affect the association between marital status and the survival of MTC, and married elders may benefit more than youngers.


A case of acute septic arthritis of the hip joint caused by Panton-Valentine leukocidin-positive ST772 community-acquired methicillin-resistant Staphylococcus aureus.
Acute septic arthritis (ASA) caused by Staphylococcus aureus can lead to fulminant arthritis and cause permanent joint destruction. In particular, infection caused by methicillin-resistant Staphylococcus aureus (MRSA) becomes intractable and severe owing to limitation of therapeutic drugs. Here, we report the case of a young patient with ASA without any record of overseas travel, who was infected by the Panton-Valentine leukocidin-positive Bengal-Bay clone, which is a predominant community-acquired MRSA in India.


The ecotoxicological effects of Photosystem II herbicides on corals.
The recent discovery of contamination of the tropical marine environment by Photosystem II (PSII) herbicides used in agriculture and antifouling paints has led to concerns regarding the effects on corals and their symbiotic dinoflagellate algae. In reviewing the ecotoxicological studies conducted so far, PSII herbicides appear able to readily penetrate the coral tissues and rapidly (within minutes) reduce the photochemical efficiency of the intracellular algal symbionts. The dinoflagellates appear at least as sensitive to PSII herbicides as other phototrophs tested so far, with photosynthesis being affected at exceptionally low concentrations (i.e. in the ngl(-1) range). At these levels and over short exposure periods, the effects can be fully reversible (i.e. when corals are returned to clean seawater) and vary according to type of herbicide; however, when exposed to higher concentrations in the light or over longer exposure periods, it results in a long-term sustained reduction of the photochemical efficiency of the algae (symptomatic of chronic photoinhibition). This can result in the dissociation of the symbiosis (bleaching) which is a common but nevertheless significant sub lethal stress response requiring many months to recover from. It is argued that the reliance of corals on an endosymbiotic photoautotrophic energy source, together with predilection for the symbiosis to dissociate when photosynthesis of the algae is affected, renders coral particularly susceptible to changes in environmental conditions-and especially phytotoxins such as PSII herbicides.


Cortex-wide Computations in Complex Decision Making in Mice.
Seemingly, a paradox exists between reports of wide-scale task-dependent cortical activity and the causal requirement for only a restricted number of motor and sensory cortical areas in some behavioral studies. In this issue of Neuron, Pinto et al. (2019) indicate that scenarios where mice must accumulate evidence and hold it during a delay period are causally linked to wide regions of cortex.


HOMBRE: A Trial Comparing 2 Weight Loss Approaches for Latino Men.
Latino men have been drastically under-represented in research to identify effective behavioral weight-loss interventions. This trial compared 2 interventions for weight loss: (1) a culturally adapted intervention (HOMBRE) and (2) a minimal-intensity intervention. Randomized controlled trial. Latino men with a BMI ≥27 kg/m2 and 1 or more cardiometabolic risk factors (N=424) were recruited (February 15, 2017‒October 2, 2018) from 14 medical centers and randomized to receive 1 of the 2 interventions. HOMBRE provided men a choice among 3 options: coach-facilitated group sessions using online video conferencing, coach-facilitated group sessions in person, and prerecorded videos of group sessions available online. The primary outcome was the proportion of participants sustaining clinically significant (≥5% of baseline) weight loss at 18 months. Secondary outcomes included weight loss trajectory over time, 3% and 10% weight loss, cardiometabolic risk factors, health behaviors, and psychosocial well-being at baseline and 18 months. Data were analyzed from October 6, 2020 to January 15, 2022. Participants were predominantly middle aged (47.0 [SD=11.9] years), were married (74.3%), were with at least some college experience (79.7%), and had middle to upper incomes (72.4% with annual family incomes >$75,000). Their average BMI was 33.1 kg/m2 (SD=5.1). The proportion achieving clinically significant weight loss at 18 months was 27.4% in the HOMBRE intervention and 20.6% in the minimal-intensity intervention (mean difference=7.2%, 95% CI= -1.8, 17.0; p=0.13). Mean difference between the HOMBRE vs the minimal-intensity group was ‒1.25 kg at 6 months (95% CI= -2.28, -0.21; p=0.02) and ‒1.11 kg at 12 months (95% CI= -2.11, -0.10; p=0.03) using weight measurement data abstracted from the Electronic Health Record and by self report. There were no significant differences in secondary outcomes. Among Latino men with overweight and obesity, HOMBRE was not more effective for clinically significant weight loss than a minimal-intensity intervention at 18 months.


Evaluation of anthoxanthins and their actions on digestive enzyme inhibition when used independently and in combination.
Carbohydrate digestibility is a key determinant for elevated postprandial hyperglycemia (PPHG). Apart from dietary restrictions, one of the strategies to reduce PPHG is to limit the activity of carbohydrate digestive enzymes within the gastrointestinal tract in order to reduce monosaccharide absorption rates. The present work aimed to assess the inhibitory capabilities of digestive enzymes (e.g., α-glucosidase and α-amylase) by anthoxanthins when used independently, in combination with acarbose, or with a different anthoxanthin. Our results showed that quercetin, myricetin, and luteolin presented lower IC50 values than acarbose and inhibited α-glucosidase through mixed-type inhibition. On the other hand, acarbose when compared with these anthoxanthins, remained the most potent inhibitor of α-amylase. Combinatorial treatment (i) acarbose-quercetin and (ii) myricetin-luteolin showed synergistic activity (CI value less than 0.9) in α-glucosidase inhibition. An additive effect (CI value between 0.9 and 1.1) in α-glucosidase inhibition was observed when acarbose-myricetin, acarbose-luteolin or when a combination of two different anthoxanthins (quercetin-myricetin and quercetin-luteolin) was used. This study suggests the potential use of anthoxanthins as functional food ingredients to mitigate PPHG towards the management of T2DM.


Anti‑Nogo‑A antibody promotes brain function recovery after cardiopulmonary resuscitation in rats by reducing apoptosis.
Brain injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is the main cause of neurological dysfunction and death in cardiac arrest. To assess the effect of Nogo‑A antibody on brain function in rats following CPR and to explore the underlying mechanisms, CA/CPR (ventricular fibrillation) rats were divided into the CPR+Nogo‑A, CPR+saline and sham groups. Hippocampal caspase‑3 levels were detected by RT‑PCR and immunoblotting. Next, Nogo‑A, glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), cysteinyl aspartate specific proteinase‑12 (casapse‑12), Bcl‑2 and Bax protein levels in the hippocampus were detected by immunoblotting. Coronal brain sections were analyzed by TUNEL assay to detect apoptosis at 72 h, while Nissl staining and electron microscopy were performed to detect Nissl bodies and microstructure at 24 h, respectively. Finally, rats were assessed for neurologic deficits at various times. Nissl staining revealed morphological improvement after Nogo‑A antibody treatment. Sub‑organelle structure was preserved as assessed by electron microscopy in model animals post‑antibody treatment; neurological function was improved as well (P<0.05), while the apoptosis index was decreased (26.2±9.85 vs. 46.6±12.95%; P<0.05). Hippocampal caspase‑3 mRNA and protein, Nogo‑A protein levels were significantly decreased after antibody treatment (P<0.05). Hippocampal Nogo‑A expression was positively correlated with caspase‑3 (Pearson's correlation; r=0.790, P=0.000). Hippocampal GRP78 and Bcl‑2 protein levels were higher after antibody treatment than these levels noted in the model animals (P<0.05), while CHOP, caspase‑12 and Bax levels were reduced (P<0.05). Nogo‑A antibody ameliorates neurological function after restoration of spontaneous circulation (ROSC), possibly by suppressing apoptosis induced by endoplasmic reticulum stress.


Clinicopathologic Significance of Heat Shock Protein 60 as a Survival Predictor in Colorectal Cancer.
The role of heat shock protein 60 (HSP60), a mitochondrial chaperone, in tumor progression or its anti-tumor effects remains controversial. This study aimed to confirm the possibility of using HSP60 as a prognostic marker in patients with colorectal cancer (CRC), considering TNM classification for precise prediction. HSP60 expression increased with differentiation and p53 mutations in patients. However, compared to patients with high HSP60 expression, patients with low HSP60 expression had event-free survival and disease-specific survival hazard ratios (HRs) of 1.42 and 1.69, respectively. Moreover, when the survival rate was analyzed by combining TNM classification and HSP60 expression, the prognosis was poor, particularly when HSP60 expression was low in the late/advanced stage. This pattern was also observed with HSP family D member 1, HSPD1, the gene that encodes HSP60. Low HSPD1 expression was linked to lower overall survival and relapse-free survival rates, with HRs of 1.80 and 1.87, respectively. When TNM classification and HSPD1 expression were considered, CRC patients with low HSPD1 expression and advanced malignancy had a poorer prognosis than those with high HSPD1 expression. Thus, HSPD1/HSP60 can be a useful biomarker for a sophisticated survival prediction in late- and advanced-stage CRC, allowing the design of individualized treatment strategies.


pH dependence of the cooperative interactions and conformation of tryptophan oxygenase.
Allosteric interactions in the cupro-heme enzyme tryptophan oxygenase (EC 18.104.22.168) of Pseudomonas acidovorans are shown to be pH-dependent. Increasing the assay pH from 6.0 to 8.0 progressively desensitizes the enzyme from both homotropic and heterotropic ligand interactions. This pH-dependent reversible transition has a pK of 6.2. Hill coefficients for the substrate L-tryptophan of 2.0 and 1.4 were measured at pH 6.0 and pH 7.0, respectively. In attempting to identify the enzymatic residue (or residues) responsible for these pH-dependent effects, the enzyme was observed to be irreversibly inactivated by photoinduced oxidation in the presence of the sensitizer, methylene blue. The photoinactivated enzyme showed a loss of one-half its Soret (405 nm) absorption which accompanied the loss of one-half its heme and histidine contents. This first order photoinduced inactivation was pH-dependent and corresponded to a requirement for a protonated species with a pK of 6.2. These results suggest that histidine residues may be involved in the catalytic function and in mediating cooperative interactions of tryptophan oxygenase. Absolute and difference sedimentation velocity analyses indicate that the molecule undergoes a conformational transition when the pH is decreased from pH 8.0 to pH 6.0. This conformational alteration, measured as a 3.9% increase in S20, w can be regarded as an equivalent decrease in the frictional coefficient. If, a more or less spherical shape to the molecule is assumed, then, the 3.9% decrease in the frictional coefficient between pH 8.0 and 6.0 corresponds to a 12% decrease in apparent hydrodynamic volume of the enzyme. Thus, protonation of an enzymatic moiety, possibly histidine, determines both the conformational and functional interactions between enzymatic sites.


Hey, Big Spender! Why Does Your Quality Lag So Far Behind Other Countries?
The United States is the world's biggest spender on health care by far. And what do we get for it? Not as much as we should. Our quality shortcomings are not for lack of knowledge: Stakeholders know what to do to close these gaps. So why aren't they doing it?


Contamination of health-care workers' hands with Escherichia coli and Klebsiella species after routine patient care: a prospective observational study.
To compare the frequency of health-care worker (HCW) hand contamination by Escherichia coli versus Klebsiella species after patient care and to determine activities associated with contamination. We conducted a prospective observational study at two tertiary-care centres. We observed HCWs caring for patients colonized/infected with E. coli or Klebsiella. HCW hands were cultured before room entry and after patient care. Contamination was defined as detecting E. coli or Klebsiella on HCW hands. Risk factors for contamination were analysed using logistic regression. Patient-to-HCW transmission was confirmed by pulsed-field gel electrophoresis (PFGE). We performed 466 HCW observations: 290 from patients with E. coli, 149 with Klebsiella, and 27 with both species. Eighty-seven per cent of observations (404/464) occurred in patients who had received chlorhexidine bathing within 2 days. HCW hand contamination rates were similar between E. coli (6.2%; 18/290) and Klebsiella (7.4%; 11/149) (p 0.6). High-risk activities independently associated with contamination were toilet assistance (OR 9.34; 95% CI 3.10-28.16), contact with moist secretions (OR 6.93; 95% CI 2.82-17.00), and hygiene/bed-bathing (OR 3.80; 95% CI 1.48-9.80). PFGE identified identical/closely related isolates in the patient and HCW hands in 100% (18/18) of E. coli and 54.5% (6/11) of Klebsiella observations. We did not find a difference in HCW hand contamination rates between E. coli and Klebsiella after patient care. Hand hygiene should be reinforced after high-risk activities. Discrepancies in matching patient and HCW hand isolates occurred more frequently for Klebsiella than for E. coli; differences in species-level transmission dynamics might exist.


Electrophysiological studies on the effect of age on caudal nerve of the rat.
The effect of age on electrophysiologic parameters was studied on the caudal nerve of 374 male Sprague-Dawley rats (age 24 to 630 days) and on 83 Fischer 344 rats (age 29 to 900 days). For Sprague-Dawley rats nerve conduction velocity and nerve action potential amplitude were both a parabolic function of age, increasing to 1 year and then declining. For Fischer 344 rats the same parameters increased progressively to 1.5 years and then declined. In contrast, for both Sprague-Dawley and Fischer 344 rats, resistance to ischemic conduction failure was a hyperbolic function of age reaching an asymptote at 1.5 to 2 years of age. These age-related changes in caudal nerve parallel the electrophysiologic alterations with age in human peripheral nerve more closely than previous reports in rodent limb nerves.


Design and evaluation of floating multi-layer coated tablets based on gas formation.
Floating multi-layer coated tablets were designed based on gas formation. The system consists of a drug-containing core tablet coated with a protective layer (hydroxypropyl methylcellulose), a gas forming layer (sodium bicarbonate) and a gas-entrapped membrane, respectively. The mechanical properties of acrylic polymers (Eudragit RL 30D, RS 30D, NE 30D) and ethylcellulose were characterized by the puncture test in order to screen a suitable film for the system. Eudragit RL 30D was chosen as a gas-entrapped membrane due to its high flexibility and high water permeability. The obtained tablets enabled to float due to the CO2-gas formation and the gas entrapment by polymeric membrane. The effect of formulation variables on floating properties and drug release was investigated. The floating tablets using direct-compressed cores had shorter time to float and faster drug release than those using wet-granulated cores. The increased amount of a gas forming agent did not affect time to float but increased the drug release from the floating tablets while increasing coating level of gas-entrapped membrane increased time to float and slightly retarded drug release. Good floating properties and sustained drug release were achieved. These floating tablets seem to be a promising gastroretentive drug delivery system.


Environmental impact of leachate characteristics on water quality.
Improper urbanization and industrialization are causing a critical stress on groundwater quality in urban areas of the developing countries. The present study under investigation describes the pollution caused by leachate from a waste management site in southwestern Bangalore city causing pollution of the surface water and groundwater reserves. The characterization of 20 groundwater samples and Haralukunte lake sample indicated high pollution of these water reserves by leachate entry into the groundwater and surface water sources. The study area focuses around the solid waste management site, carrying out bio-composting and vermi-composting of municipal solid waste. Further investigations on the severe health problems faced by the public in the study area has revealed a clear pointer towards the usage of polluted water for rearing live-stock, farming, and domestic activities. The characterization of the leachate with high values of BOD at 1,450 mg/l, TDS at 17,200 mg/l, nitrates at 240 mg/l, and MPN at 545/100 ml indicates a clear nuisance potential, which has been substantiated by the characterization of lake water sample with chlorides at 3,400 mg/l, TDS at 8,020 mg/l, and lead and cadmium at 0.18 and 0.08 mg/l, respectively. Analysis of groundwater samples shows alarming physicochemical values closer to the waste disposal site and relatively reduced values away from the source of the waste management site. Bureau of Indian Standards have been adapted as the benchmark for the analysis and validation of observed water quality criteria.


Aflatoxin contamination of Nigerian foods and feedingstuffs.
Human foods and animal feeds, and ingredients used for their preparation or formulation in Nigeria, were surveyed between 1988 and 1991 for the presence of the fungal metabolite and animal carcinogen aflatoxin. Groundnut and groundnut-containing materials were the most heavily contaminated, the highest value (1862 ppb) being found in a groundnut cake sample. This mycotoxin was also detected occasionally, but to a lesser extent, in some grains and cereals that are of nutritional importance in human foods and the livestock industry in Nigeria. The toxicological implications of this finding are discussed in relation to human health and animal production.


A systematic review of the evidence on home care reablement services.
To determine whether publically funded 'reablement services' have any effect on patient health or use of services. Systematic review of randomized controlled trials and non-randomized studies in which reablement interventions were compared with no care or usual care in people referred to public-funded personal care services. Data sources included: Cochrane Central Register of Controlled Trials, EPOC register of studies, trials registers, Medline, EMBASE, and CINHAL. Searches were from 2000 up to end February 2015. Not applicable. Investigators' definition of the target population for reablement interventions. Use of publically funded personal care services and dependence in personal activities of daily living. We found no studies fulfilling our inclusion criteria that assessed the effectiveness of reablement interventions. We did note the lack of an agreed understanding of the nature of reablement. Reablement is an ill-defined intervention targeted towards an ill-defined and potentially highly heterogeneous population/patient group. There is no evidence to suggest it is effective at either of its goals; increasing personal independence or reducing use of personal care services.


Enkephalin precursor gene expression in postmeiotic germ cells.
Preproenkephalin mRNA was detected in rat testis after postnatal day 30. A high abundance of preproenkephalin mRNA was present in the spermatids (i.e., spermatogenic cells at postmeiotic stage) purified from mature rat testis. The mRNA size of the spermatids was about 1900 bases, which was larger than that of other tissues expressing the preproenkephalin gene. The spermatids contained small amounts of enkephalin-containing proteins, but little or no Met-enkephalin. Preproenkephalin gene expression in the germ cells suggests the connection between gametogenesis and nervous system.


Cannabinoid CB₂ receptors are involved in the regulation of fibrogenesis during skin wound repair in mice.
Studies have shown that cannabinoid CB2 receptors are involved in wound repair, however, its physiological roles in fibrogenesis remain to be elucidated. In the present study, the capacity of cannabinoid CB2 receptors in the regulation of skin fibrogenesis during skin wound healing was investigated. To assess the function of cannabinoid CB2 receptors, skin excisional BALB/c mice were treated with either the cannabinoid CB2 receptor selective agonist, GP1a, or antagonist, AM630. Skin fibrosis was assessed by histological analysis and profibrotic cytokines were determined by immunohistochemistry, immunofluorescence staining, reverse transcription‑quantitative polymerase chain reaction and immunoblotting in these animals. GP1a decreased collagen deposition, reduced the levels of transforming growth factor (TGF)‑β1, TGF‑β receptor I (TβRI) and phosphorylated small mothers against decapentaplegic homolog 3 (P‑Smad3), but elevated the expression of its inhibitor, Smad7. By contrast, AM630 increased collagen deposition and the expression levels of TGF‑β1, TβRI and P‑Smad3. These results indicated that cannabinoid CB2 receptors modulate fibrogenesis and the TGF‑β/Smad profibrotic signaling pathway during skin wound repair in the mouse.


Programmed death-ligand 1 (PD-L1) expression in cervical intraepithelial neoplasia and cervical squamous cell carcinoma of HIV-infected and non-infected patients.
Programmed death-ligand 1 (PD-L1) is overexpressed in cervical carcinoma, hindering tumor destruction. The aim of this study was to assess PD-L1 expression by immunohistochemistry in cervical squamous cell carcinoma (SCC) and squamous intraepithelial lesions (SILs) from human immunodeficiency virus-positive (HIV+) and human immunodeficiency virus-negative (HIV-) patients. A total of 166 SCC and SIL samples of HIV+ and HIV- patients were included and analyzed for PD-L1 expression through tumor proportion score (TPS), and results were stratified in five TPS groups using SP263 antibody and, combined positive score (CPS) using 22C3 antibody. In cohort 1 (SP263 clone), all HIV+ patients were negative for intraepithelial lesion or malignancy (NILM), and low-grade squamous intraepithelial lesions (LSILs) scored < 1; and 87.5% of high-grade squamous intraepithelial lesions (HSILs) adjacent to SCC, 19% of HSILs non-adjacent to SCC, and 69% of SCCs scored ≥ 1 (15.4% scored 5). In HIV- patients, all NILM, LSILs, HSILs adjacent to SCC, and two HSILs non-adjacent to SCC scored < 1. SCC: 88.2% scored ≥ 1 and 5.9% scored 5. In cohort 2 (SP263 and 22C3 clones), 16.7% of HIV+ patients with SCC were positive with both clones, CPS ≥ 1 (22C3) or score 5 (≥ 50%) (SP263), showing no significant differences in positivity between both clones. These results indicate that a relatively low percentage of SCCs (16.7%; both in HIV+ and in HIV- patients) express PD-L1 (TPS ≥ 50% and CPS > 1), which may be due to some samples being archival material, sample characteristics, or use of different methodologies, highlighting the need for standardization of PD-L1 assessment in SCC of the cervix. The fact that PD-L1 is overexpressed in SILs of HIV+ patients suggests potential additional applications for immunotherapy in this disease.


Cell death in the developing retinal ganglion cell layer of the wallaby Setonix brachyurus.
The distribution and number of dying cells in the developing retinal ganglion cell layer of the wallaby Setonix brachyurus were assessed by using cresyl violet stained tissue. The density of dying cells has been expressed per 100 live cells for the entire retinal surface, data being presented as a grid of 500 micron squares. For statistical analysis, retinae were divided into 8 regions; dorsal, ventral, nasal, and temporal quadrants, each further divided into center and periphery. This method allowed comparison of the extent of cell death at different retinal locations as the high density area centralis of live cells developed temporal to the optic disk from 60 days onward. Between 30 and 70 days, dying cells were seen across the entire retina; beyond 100 days very few were seen. Initially, there was a significantly higher incidence of dying cells in the central retina compared to the periphery, whereas from 50 days this situation was reversed. Analysis of the central retina before and during area centralis formation consistently indicated a significantly lower number of dying cells per 100 live cells in temporal compared to other retinal quadrants. This differential pattern suggests that cell death lowers live cell densities less in the emerging area centralis than elsewhere, and therefore must play a part in establishing live cell density gradients. However, we cannot exclude the possibility that other factors are also instrumental. Indeed, factors such as areal growth (Beazley et al., in press) presumably operate at later stages since live cell density gradients continue to be accentuated even after cell death is complete. Numbers of dying cells peaked by 50 days, reaching approximately 1% of the live cell population. At this stage, counts were also maximal for live cells with values up to 30% above the adult range.


Short-term trivalent arsenic and hexavalent chromium exposures induce gut dysbiosis and transcriptional alteration in adipose tissue of mice.
Inorganic arsenic [As(III)] and hexavalent chromium [Cr(VI)] can potentially affect metabolic functions. These heavy metal(s)/metalloids can also affect the gut microbial architecture which affects metabolic health. Here, we assessed the effects of short-term exposure of As(III) and Cr(VI) on key transcription factors in adipose tissues and on selected gut microbial abundances to understand the possible modulatory role of these toxicants on host metabolic health. qRT-PCR based relative bacterial abundance studies in cecal samples, gene expression analysis for gut wall integrity in ileum and colon and adipogenesis, lipolysis, and thermogenic genes in gonadal white and brown adipose tissue (gWAT and BAT), along with tissue oxidative stress parameters have been performed. As(III) and Cr(VI) exposure reduced beneficial Lactobacilli, Bifidobacteria, Akkermansia, Lachenospiraceae, Fecalibacterium, Eubacterium, and clostridium coccoid group while increasing lipopolysaccharides producing Enterobacteriaceae abundances. It also impaired structural features and expression of key tight junction and mucin production genes in ileum and colon (Cld-2, Cld-4, ZO-1, ZO-2, MUC-2 and - 4). In gWAT it inhibited adipogenesis (PPARγ, FASN, SREBP1a), lipolysis (HSL, ACOX-1), and thermogenesis (UCP-1, PGC1a, PRDM-16, PPARa) related genes expression, whereas in BAT, it enhanced adipogenesis and reduced thermogenesis. These exposures also reduces the endogenous antioxidants levels in these tissues and promote pro-inflammatory cytokines genes expression (TLRs, IL-6, MCP-1). The combinatorial exposure appears to have more deleterious effects. These effects of As(III) and Cr(VI) may not directly be linked to their known toxicological effects, instead, more intriguing crosstalk with gut microbial ecosystem hold the key.


Effect of surgery for endometrioma on ovarian function: a different point of view.
Recent evidence in the literature suggests that surgical excision of the endometrioma wall may reduce ovarian reserve, which may have a negative effect on subsequent reproductive function. However, because of inconsistent results and methodologic flaws of anti-müllerian hormone (AMH) as a marker of ovarian reserve, antral follicle count may be a more accurate noninvasive marker than AMH. Evaluating ovarian reserve using antral follicle count rather than AMH may yield different conclusions insofar as postsurgical damage to the ovary. Surgery should be performed only by experienced surgeons, and the stripping technique currently is still the only one supported by strong scientific evidence. The dual function of surgery, that is, to improve fertility and reduce pain, cannot be minimized or undervalued.


Necrotizing lymphadenitis. Case report and review of the literature.
A 22-year-old Jordanian woman with enlarged cervical lymph nodes proved histologically to be suffering from necrotizing lymphadenitis; she recovered spontaneously. She had remained in good health at four years follow up. This is the first case reported from Jordan. The clinical picture, etiology, histopathology, course and differential diagnosis of the disorder are discussed.


White Matter Changes Associated with Resting Sympathetic Tone in Frontotemporal Dementia vs. Alzheimer's Disease.
Resting sympathetic tone, a measure of physiological arousal, is decreased in patients with apathy and inertia, such as those with behavioral variant frontotemporal dementia (bvFTD) and other frontally-predominant disorders. To identify the neuroanatomical correlates of skin conductance levels (SCLs), an index of resting sympathetic tone and apathy, among patients with bvFTD, where SCLs is decreased, compared to those with Alzheimer's disease (AD), where it is not. This study analyzed bvFTD (n = 14) patients and a comparison group with early-onset AD (n = 19). We compared their resting SCLs with gray matter and white matter regions of interest and white matter measures of fiber integrity on magnetic resonance imaging and diffusion tensor imaging. As expected, bvFTD patients, compared to AD patients, had lower SCLs, which correlated with an apathy measure, and more gray matter loss and abnormalities of fiber integrity (fractional anisotropy and mean diffusivity) in frontal-anterior temporal regions. After controlling for group membership, the SCLs were significantly correlated with white matter volumes in the cingulum and inferior parietal region in the right hemisphere. Among dementia patients, SCLs, and resting sympathetic tone, may correlate with quantity of white matter, rather than with gray matter or with white matter fiber integrity. Loss of white matter volumes, especially involving a right frontoparietal network, may reflect chronic loss of cortical axons that mediate frontal control of resting sympathetic tone, changes that could contribute to the apathy and inertia of bvFTD and related disorders.


Immunological dysfunction in Alzheimer's disease.
Peripheral blood lymphocytes from Alzheimer's patients and apparently healthy elderly individuals were examined for interleukin-1 (IL-1) production. Our results indicate severely low production of IL-1 by patient's peripheral blood monocytes. The low production of IL-1 in vitro correlated with patients' symptoms and therapy with 1-acetamide,2-pyrrolidone (1a,2p). In addition to low IL-1 production, the number of autologous rosette forming cells (ARFC) was significantly decreased in all Alzheimer's patients whereas B-cell glucose metabolism was significantly higher than age-matched healthy individuals.


Diurnal variation on tear stability and correlation with tear cytokine concentration.
To investigate the effect of time of day on tear evaporation rate (TER) and tear break-up time, and its possible relationship with the concentration of inflammatory tear molecules (cytokines) in healthy subjects. Participants with healthy ocular surfaces attended 3 visits, including the screening visit (V0), the 2nd visit (V1) and the 3rd visit (V2). There were 7-day intervals between visits. Participants with Dry Eye Disease (DED) were excluded by using appropriate clinical tests during V0. Clinical evaluation (TER and Non-Invasive Tear Break-Up Time (NITBUT)) and tear collection were performed during V1 and V2, between 9 and 10AM and 3-4PM. The relative humidity and temperature of the examination room were also measured. The tear fluid concentrations of 15 cytokines were measured by multiplex bead analysis. Seven men and 10 women (mean age ± S.D; 25.1 ± 6.63 years old) participated in the study. There were no differences in neither the TER and NITBUT outcomes, nor humidity and temperature among times or visits. Eleven out of the 15 cytokines measured were detectable in tear fluids in > 50% of the participants. In the tear levels, no significant (p > 0.05) inter- and/or intra-day differences were detected for EGF, fractalkine, IL-1RA, IL-1β and IP-10. However, significant inter-day differences were found in the tear levels of IL-10 (p = 0.027), IFN-γ (p = 0.035) and TNF-α(p = 0.04) and intra-day differences in the tear levels of IL-8/CXCL8 (p = 0.034) and MCP-1 (p = 0.002). A significant correlation between TER and IL1-β, IL-2, and Fractalkine (p = 0.03, p = 0.03 and p = 0.046, respectively) was found at V1. NITBUT and TER values had no significant variability over the course of a day (AM versus PM), or on different days in healthy participants when humidity and temperature were constant. However, some tear molecule levels did show inter- and intra-day variability, having an inconsistent and moderate correlation with TER diurnal variation.


Learning binds new inputs into functional synaptic clusters via spinogenesis.
Learning induces the formation of new excitatory synapses in the form of dendritic spines, but their functional properties remain unknown. Here, using longitudinal in vivo two-photon imaging and correlated electron microscopy of dendritic spines in the motor cortex of mice during motor learning, we describe a framework for the formation, survival and resulting function of new, learning-related spines. Specifically, our data indicate that the formation of new spines during learning is guided by the potentiation of functionally clustered preexisting spines exhibiting task-related activity during earlier sessions of learning. We present evidence that this clustered potentiation induces the local outgrowth of multiple filopodia from the nearby dendrite, locally sampling the adjacent neuropil for potential axonal partners, likely via targeting preexisting presynaptic boutons. Successful connections are then selected for survival based on co-activity with nearby task-related spines, ensuring that the new spine preserves functional clustering. The resulting locally coherent activity of new spines signals the learned movement. Furthermore, we found that a majority of new spines synapse with axons previously unrepresented in these dendritic domains. Thus, learning involves the binding of new information streams into functional synaptic clusters to subserve learned behaviors.


Diaphragmatic endometriosis: diagnosis, surgical management, and long-term results of treatment.
To describe symptoms, surgical diagnosis and treatment, and long-term outcome of patients with symptomatic diaphragmatic endometriosis. Observational follow-up study. American tertiary referral center for the surgical treatment of endometriosis. Eight patients with diaphragmatic endometriosis causing severe or disabling symptoms. Laparoscopic diagnosis of diaphragmatic endometriosis followed by upper abdominal laparotomy for full-thickness resection of the diaphragm. Reduction of several symptoms as measured on a 5-point ranked ordinal scale administered by a phone survey up to 7 years after surgery. Laparoscopy from an umbilical port may identify small "sentinel lesions" of endometriosis on the anterior or mid diaphragm. Eight symptomatic patients all had significant invasive disease with dimensions up to 5 cm across of the posterior right diaphragm, which could not always be seen from the umbilical port site. All such lesions can be seen by a laparoscope placed beneath the right costal margin. Laparoscopic treatment of symptomatic disease is not rational given the posterior placement of the disease out of sight behind the liver and the full-thickness nature of the disease in all eight patients. Laparotomy with full thickness resection of the diaphragm resulted in complete eradication of symptoms in seven of eight patients, and good symptomatic reduction in one. Treatment of diaphragmatic endometriosis by laparotomy results in a high rate of symptom relief. Laparoscopic treatment of diaphragmatic endometriosis will result in a high rate of incomplete diagnosis and incomplete treatment with a high rate of continuing symptoms.


Expression of CD16, CD18 and CD56 in tributyltin-exposed human natural killer cells.
Tributyltin (TBT) was produced in large quantities for use in wood preservation, marine antifouling paints, disinfection of circulating industrial cooling waters and slime control in paper mills. TBT is found in dairy products, meat and fish. We and others have shown that there are measurable levels of TBT in human blood. BTs appear to increase the risk of cancer and viral infections in exposed individuals. In previous studies, we demonstrated that the NK-cytotoxic function of lymphocytes was greatly diminished after a 1-h exposure to 300 nM TBT or a 24-h exposure to 200 nM TBT. Inhibition induced by a 1-h exposure to 300 nM TBT continues even after removal of the compound. There is also decreased ability of NK cells to bind to tumor target cells when they have been exposed to 200 nM TBT for 24 h. This loss of binding function is not seen when NK cells are exposed to 300 nM TBT for 1 h. However, NK cells exposed to 300 nM TBT for 1 h and then incubated in TBT-free media for 24, 48 or 96 h, show a significant loss of tumor-binding function by 96 h. The effects of TBT on cell surface molecules that are crucial to NK cell function is investigated. The data indicate there is a loss of expression of CD16 and CD56 on NK cells exposed to 200 nM TBT for 24 h. There is no decrease in expression of any of the markers studied when NK cells are exposed to 300 nM TBT for 1 h, consistent with the fact that a 1-h exposure has no effect on the ability of NK cells to bind to tumor targets. However, when NK cells are exposed to 300 nM TBT followed by 24, 48 or 96 h incubations in TBT-free media, there is a significant loss of CD16 and CD18 expression after 24 h and of CD16 and CD56 expression after 48 and 96 h.


Economic and environmental impacts on ports and harbors from the convention to ban harmful marine anti-fouling systems.
The recent Diplomatic Conference held (1-5 October 2001) by the International Maritime Organization (IMO) in London adopted the Draft Convention prepared by The Marine Environmental Protection Committee (MEPC) of IMO for the "Control of Harmful Anti-fouling Systems for Ships." The convention has been developed to immediately ban the use of Tributyltin (TBT) globally in anti-fouling paints to "protect the marine environment". The ban on TBT has come about because TBT has detrimental effects on non-target marine organisms. In November 1999, IMO agreed that a treaty be developed by the MEPC to ensure a ban on the application of TBT based anti-fouling paints by 1 January 2003, and a ban on the use of TBT by 1 January 2008. At the meeting surious concern was expressed by some experts for the need to identify in the treaty the necessary regulatory language for: (1) the "safe" removal, treatment, and disposal of marine anti-foulants deemed "harmful" by the treaty and (2) who is liable for the future dredging and disposal of TBT-contaminated port and harbor sediments--to also "protect the marine environment". The requirement for "safe" removal and disposal was incorporated at MEPC 46 as Article 5 in the treaty, without it shipyards complying with existing national and local discharge regulations (most have none for discharge of TBT) could inadvertently release more TBT to ports and harbors in the five-year compliance period than has been leached from ships (hulls) in the past 40 years to the same waters. Virginia is the only State in the US that regulates the discharge to below 50 ng/l (50 parts per trillion). However, the liability for the future dredging and disposal costs of TBT-contaminated port and harbor sediments has not been addressed.


Remediation of cadmium contaminated soil using K2FeO4 modified vinasse biochar.
The remediation of cadmium (Cd) contaminated soil is challenging for agricultural practices. In this study, a novel vinasse biochar modified by potassium ferrate (K2FeO4) was synthesized to immobilize Cd in agricultural soil. Three biochars [i.e., vinasse biochar (BC), KMnO4 modified vinasse biochar (MnBC), and K2FeO4 modified vinasse biochar (FeBC)] were applied to compare their efficiencies of Cd immobilization. The results showed that the orders of pH, ash content, and functional groups in different biochar were the same following BC < MnBC < FeBC. Scanning electron microscope images showed that the FeBC has more micropores than MnBC and BC. X-ray diffraction identified manganese oxides and iron oxides within MnBC and FeBC, indicating that Mn and Fe were well loaded on the biochar. In the soil-based pot experiment, both MnBC and FeBC significantly reduced soil available Cd by 23-38% and 36-45% compared with the control, respectively (p < 0.05). In addition, the application of BC, MnBC, and FeBC significantly increased the yield, chlorophyll, and vitamin C of Chinese cabbage (p < 0.05), and decreased its Cd uptake compared with the control. Notably, shoot Cd significantly reduced when 2% FeBC was applied (p < 0.05). Overall, using K2FeO4 to modify vinasse biochar enriched the surface functional groups and minerals as well as reduced Cd availability in soil and its uptake by the plant. Our study showed that K2FeO4 modified vinasse biochar could be used as an ideal amendment for the remediation of Cd-contaminated soil.


A comparison of external and self-instructional teaching formats with mentally retarded adults in a vocational training setting.
A theory recently proposed by Whitman postulates that self-instructional training procedures should have special utility for low ability individuals. Although past studies have shown that self-instructional training programs can be employed to improve the performance of mentally retarded individuals in work situations, research has not examined whether this training format is superior to external instruction. To test Whitman's theory, mentally retarded adults were taught to perform a complex sequencing task through one of two training formats: self-instruction or external instruction. Performance was evaluated through the examination of accuracy measures obtained during training, maintenance, and generalization assessments. Results indicated that participants receiving self-instructional training were able to achieve and sustain a higher level of performance than participants receiving external instruction. While self-instructionally trained subjects also showed superior performance on the generalization assessment, these results were not statistically significant. Secondary analyses revealed that higher ability participants, self-instructionally trained participants, and participants who reached criterion on the training and generalization tasks self-verbalized more frequently during the various assessments. In contrast to prediction, there was no significant difference in the length of time required to train individuals in the two instructional groups.


Circ_0037078 promotes trophoblast cell proliferation, migration, invasion and angiogenesis by miR-576-5p/IL1RAP axis.
Preeclampsia (PE) is a common hypertensive disorder of pregnancy. Recent studies have suggested that circular RNAs (circRNAs) play a pathological role in PE. Herein, this study aimed to investigate the action and mechanism of circ_0037078 in PE process. The quantitative real-time PCR (qRT-PCR) and Western blot were used to determine the expression levels of RNAs and genes. Cell proliferation, migration, invasion and angiogenesis were evaluated by using cell counting kit-8 (CCK-8), colony formation, transwell, and tube formation assays, respectively. The target relation between miR-576-5p and IL1RAP (Interleukin-1 receptor accessory protein) and circ_0037078 was predicted by bioinformatics analysis and verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Circ_0037078 expression was higher in placental tissues of patients with PE than that of normal control. Knockdown of circ_0037078 led to an enhancement of the proliferation, migration, invasion, and angiogenesis in trophoblast cells. Mechanistically, circ_0037078 acted as a sponge for miR-576-5p, thus elevating the expression of IL1RAP, which was targeted by IL1RAP. Further rescue experiments suggested that miR-576-5p inhibition reversed the effects of circ_0037078 knockdown on above behaviors of trophoblast cells. Moreover, miR-576-5p overexpression enhanced the proliferative, migratory, invasive, angiogenic phenotypes of trophoblast cells, which were attenuated by IL1RAP up-regulation. Circ_0037078 knockdown promotes trophoblast cell proliferation, migration, invasion, and angiogenesis in vitro by miR-576-5p/IL1RAP axis, providing a novel insight into the etiology of PE.


Antisaccade-related brain activation in children with attention-deficit/hyperactivity disorder--A pilot study.
While antisaccade paradigms invoke circuitry associated with cognitive control and attention-deficit/hyperactivity disorder (ADHD), there is a dearth of functional magnetic resonance imaging (fMRI) investigations using antisaccade tasks among children with ADHD. Neural correlates associated with antisaccade performance were examined with fMRI in 11 children with ADHD (10 medicated) matched to 11 typically developing children. Significantly greater brain activation in regions in right dorsolateral prefrontal cortex and caudate nucleus was observed in children with ADHD relative to the control group. This pattern separated the children into their respective groups in a taxonomic manner. Sensitivity analyses probing comorbidity and medication-specific effects showed that results were consistent; however, the caudate nucleus difference was only detectable in the full sample, or in subsets with a more relaxed cluster threshold. Antisaccade performance did not significantly differ between the groups, perhaps as a result of greater brain activation or medication effects in the ADHD group. Thus, antisaccade paradigms may have sensitivity and specificity for the investigation of cognitive control deficits and associated neural correlates in ADHD, and may contribute towards the development of new treatment approaches for children with the disorder.


Anti-inflammatory adipokines: chemerin, vaspin, omentin concentrations and SARS-CoV-2 outcomes.
Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation. A wide range of adipokines activities suggests they influence pathogenesis and infection course. The aim was to assess concentrations of chemerin, omentin, and vaspin among COVID-19 patients with an emphasis on adipokines relationship with COVID-19 severity, concomitant metabolic abnormalities and liver dysfunction. Serum chemerin, omentin and vaspin concentrations were measured in serum collected from 70 COVID-19 patients at the moment of admission to hospital, before any treatment was applied and 20 healthy controls. Serum chemerin and omentin concentrations were significantly decreased in COVID-19 patients compared to healthy volunteers (271.0 vs. 373.0 ng/ml; p < 0.001 and 482.1 vs. 814.3 ng/ml; p = 0.01, respectively). There were no correlations of analyzed adipokines with COVID-19 severity based on the presence of pneumonia, dyspnea, or necessity of Intensive Care Unit hospitalization (ICU). Liver test abnormalities did not influence adipokines levels. Elevated GGT activity was associated with ICU admission, presence of pneumonia and elevated concentrations of CRP, ferritin and interleukin 6. Chemerin and omentin depletion in COVID-19 patients suggests that this adipokines deficiency play influential role in disease pathogenesis. However, there was no relationship between lower adipokines level and frequency of COVID-19 symptoms as well as disease severity. The only predictive factor which could predispose to a more severe COVID-19 course, including the presence of pneumonia and ICU hospitalization, was GGT activity.


Dual regulation of 21-hydroxylase activity by sex steroid hormones in rat hepatocytes.
In the rat liver, cytochrome P450 catalyzes the hydroxylation of steroid hormones. The expression and activity of some P450 isozymes are regulated by sex steroid hormones. Steroid 21-hydroxylase activity in rat liver is provided mainly by CYP2C6. We studied the regulation of 21-hydroxylase activity by sex steroid hormones in rat primary hepatocyte culture. We added estrogens (estrone, estradiol, estriol) and androgens (testosterone, dihydrotestosterone), (ranging from 10(-9) to 10(-5)M) to the culture. The 21-hydroxylase activity was stimulated by estrogens and was suppressed slightly by androgen in a dose-related manner. The results of our studies demonstrated that sex steroid hormones act differently on 21-hydroxylase activity in rat hepatocytes and, thus, support the hypothesis that the extra-adrenal production of deoxycorticosterone from circulating progesterone is increased during pregnancy by the massive presence of estrogens.


The yin and yang of the exosome.
Recent studies of the eukaryotic ribosomal RNA processing pathway have identified a complex of ten riboexonucleases called the exosome that plays a central role in the precise formation of the 3' ends of several types of RNAs. The exosome also destroys excess ribosomal RNA precursors and unused intermediates and degrades poly(A)-mRNAs in the cytoplasm. In the nucleus, the complex appears to function in a regulated mRNA surveillance system that degrades transcripts in response to defects in the mRNA processing and export pathways. How the cell regulates the nucleolytic prowess of the exosome to ensure correct and timely synthesis and destruction of RNAs is a central focus of current research.


[Garden I femoral neck fractures: conservative vs operative therapy].
Treatment recommendations vary for Garden I fractures of the proximal femur. The aim of our retrospective study was to determine the results of functional treatment of these injuries. A total of 54 consecutive patients were enrolled, and their data (age, comorbidities, treatment, complications, etc.) were ascertained and stored in a database. Initial treatment consisted in early mobilization and weight bearing in all patients. In 24 cases (44%) no complications at all were observed in the course of conservative treatment. In 28 cases (52%) surgical treatment was necessary due to early fracture dislocation. Analysis of the X-ray images showed that in 9 of these 28 cases the functional treatment had not been clearly indicated, i.e., incomplete impaction of the fragments. When these patients are excluded the success rate of conservative treatment was 53%, as two additional late complications occurred and were treated surgically (1x AVN, 1x nonunion). With reference to the survival rate, score, and patient satisfaction, there was no difference between conservative and operative treatment (p=0.478). The risk of a secondary dislocation increases with the number of risk factors (p=0.008). An attempt at functional treatment with close X-ray monitoring is appropriate in these fractures, since this makes it possible to avoid surgery in about half of the patients while achieving functional results comparable to those yielded by surgery.


Selective PKC beta inhibition with ruboxistaurin and endothelial function in type-2 diabetes mellitus.
Type-2 diabetes mellitus increases risk of atherosclerotic cardiovascular disease. However, the mechanisms linking hyperglycemia and atherosclerosis remain poorly understood. One proposed mechanism involves endothelial dysfunction via activation of protein kinase C beta (PKC beta). Prior studies demonstrate beneficial effects of PKC beta inhibition on microvascular parameters, but, to date, no study has examined the effect on macrovascular atherosclerotic readouts. The goal of this double-masked, placebo-controlled trial in type-2 diabetes was to assess the effect of the PKC beta-specific inhibitor, ruboxistaurin (32 mg/day for 6 weeks) on ultrasound assessed brachial artery flow mediated dilatation (FMD), a surrogate of macro vascular endothelial function, and urinary isoprostanes, indices of oxidant stress. Compared to placebo, ruboxistaurin tended to improve FMD (difference in 6-week change in FMD, mean +/- SD millimeter) at one (0.13 +/- 0.26 mm, p = 0.08) and 5 min (0.12 +/- 0.21 mm, p = 0.02) after cuff deflation, but had no effect on nitroglycerin-mediated dilatation or urinary isoprostanes. This proof of concept trial is the first to suggest that specific inhibition of PKC beta may improve macro vascular endothelial function in type-2 diabetes. Larger trials including clinical endpoints are warranted to determine the potential efficacy of PKC beta inhibition in reducing atherosclerotic cardiovascular complications in diabetes mellitus.


Cyclosporine and skin allografts for the treatment of thermal injury. I. Extensive graft survival with low-level long-term administration and prolongation in a rat burn model.
The hypothesis tested in the present and accompanying study is that an effective treatment for severe burns involves early excision of necrotic tissue followed by skin allografting and cyclosporine (CsA) immunosuppressive therapy. LEW (RT1) rats served as recipients of thermal injury and/or skin allografts. BN x LEW F1 (LBN, RT1(l+n)) rats served as skin donors. LEW burn recipients received a hot water (90 degrees C for 10 sec) 30% body surface area (BSA) full-thickness burn. As expected, LEW recipients treated with CsA (25 mg/kg/day for 20 days) demonstrated significant graft prolongation compared with controls (P less than 0.005). Skin graft survival was similarly prolonged in LEW recipients undergoing burn injury, primary wound excision, and CsA administration compared with burn-skin allograft controls (P less than 0.001). Mortality was not increased in the thermal injury-CsA-treated recipients compared with burn controls. A final experiment was initiated to investigate how low-level long-term (greater than 100 days) maintenance CsA treatment influenced skin allograft survival for possible future consideration in burn trauma. Recipients receiving skin allografts plus CsA (20 days, 8mg/kg/day, followed by every other day thereafter) did not reject their grafts. However, a possible early sign of rejection (a single small ulcerative lesion) was noted in five of these long-term CsA-treated animals at a mean of 34 +/- 11 (SD) days. The lesion in these animals did not progress any further during CsA administration. Histopathologic study of selected animals removed from the CsA maintenance regimen for greater than 50 days following long-term administration revealed a number of interesting chronic lesions similar to those previously reported in the skin component of composite tissue (limb) allografts following long-term low-level CsA intervention. In conclusion, CsA was very successful in preventing rejection of skin allografts in a rat burn model without apparent adverse effects.


A Population Representation of Absolute Light Intensity in the Mammalian Retina.
Environmental illumination spans many log units of intensity and is tracked for essential functions that include regulation of the circadian clock, arousal state, and hormone levels. Little is known about the neural representation of light intensity and how it covers the necessary range. This question became accessible with the discovery of mammalian photoreceptors that are required for intensity-driven functions, the M1 ipRGCs. The spike outputs of M1s are thought to uniformly track intensity over a wide range. We provide a different understanding: individual cells operate over a narrow range, but the population covers irradiances from moonlight to full daylight. The range of most M1s is limited by depolarization block, which is generally considered pathological but is produced intrinsically by these cells. The dynamics of block allow the population to code stimulus intensity with flexibility and efficiency. Moreover, although spikes are distorted by block, they are regularized during axonal propagation.


Indications for islet or pancreatic transplantation: Statement of the TREPID working group on behalf of the Société francophone du diabète (SFD), Société francaise d'endocrinologie (SFE), Société francophone de transplantation (SFT) and Société française de néphrologie - dialyse - transplantation (SFNDT).
While either pancreas or pancreatic islet transplantation can restore endogenous insulin secretion in patients with diabetes, no beta-cell replacement strategies are recommended in the literature. For this reason, the aim of this national expert panel statement is to provide information on the different kinds of beta-cell replacement, their benefit-risk ratios and indications for each type of transplantation, according to type of diabetes, its control and association with end-stage renal disease. Allotransplantation requires immunosuppression, a risk that should be weighed against the risks of poor glycaemic control, diabetic lability and severe hypoglycaemia, especially in cases of unawareness. Pancreas transplantation is associated with improvement in diabetic micro- and macro-angiopathy, but has the associated morbidity of major surgery. Islet transplantation is a minimally invasive radiological or mini-surgical procedure involving infusion of purified islets via the hepatic portal vein, but needs to be repeated two or three times to achieve insulin independence and long-term functionality. Simultaneous pancreas-kidney and pancreas after kidney transplantations should be proposed for kidney recipients with type 1 diabetes with no surgical, especially cardiovascular, contraindications. In cases of high surgical risk, islet after or simultaneously with kidney transplantation may be proposed. Pancreas, or more often islet, transplantation alone is appropriate for non-uraemic patients with labile diabetes. Various factors influencing the therapeutic strategy are also detailed in this report.


Nerve transplantation shows that motor end-plate disease is not a primary Schwann cell defect.
Motor end-plate diseased (MED) mice have altered nerve impulse conduction velocities and refractory periods. To test whether these pathological properties are caused by a primary Schwann cell defect, nerves were transplanted from MED and wildtype (WT) animals onto WT recipients. The donor origin of cells in the regenerated nerve was assessed by prelabeling with [3H]thymidine and by electrophoretic analysis of glucose phosphate isomerase allotypes. Nerve fiber regeneration through MED and WT implants was equally efficient. No difference was found in nerve conductivities of MED and WT grafts. Therefore a primary defect in the Schwann cells of the MED mouse is unlikely.


[Characteristics of bacteria of the genus Citrobacter, isolated from healthy children and children with different acute gastrointestinal diseases].
The authors examined 250 children suffering from various acute gastrointestinal diseases, and 100 healthy children. Positive cultures of bacteria belonging to the Citrobacter genus were obtained in 38% of the patients and in 20% of the healthy persons. There were revealed no cultural or biochemical differences between the strains isolated from the sick and healthy individuals. There were revealed no cultural or biochemical differences between the strains isolated from the sich and healthy persons. A total of 189 strains were identified serologically. Serological types 01, 03, 04, 08, 021, 022, the ones most frequently encountered in sick children, were absent or rarely found in the healthy. Sensitivity of the majority of the strians to the main antibiotics used in medical practice was weak; the strain isolated from the sick and healthy children failed to differ by the antibiotic sensitivity.


Characterization of the three 125I-iodination isomers of human insulin-like growth factor I (IGF1).
Human insulin-like growth factor I (IGF1) was labeled with 125I and the resulting mixture of iodination isomers was separated by reverse-phase HPLC. Three major radioactive peaks were isolated and identified by sequencing as the expected three monoiodinated species. The ranking of the affinities of the three isomers for the human IGF1 receptor was found to be Tyr24(125I) > Tyr31(125I) >> Tyr60(125I). The Tyr31(125I) isomer was shown to have an affinity similar to that of unlabeled IGF1 and is thus the tracer of choice for IGF1. The tracers were stable upon storage at -20 degrees C for at least 3 months.