Increased total mortality as a function of 24-h pulse pressure dipping.
Elevated pulse pressure (PP) as a difference between systolic and diastolic blood pressure is a significant risk factor of cardiovascular (CV) diseases. The goal of our study was to determine the association between PP and major adverse CV events (MACEs), and all-cause and CV mortality in the different age groups of patients with coronary artery disease (CAD) confirmed by angiography. To the PROGNOSIS study, finally there were included 891 subjects with CAD. An analysis of the receiver operating characteristic was used for predicting PP dipping among the age groups of patients. A COX proportional hazards model was used to examine the association between PP and PP dipping and risk of MACE, revascularization, CV and total mortality after adjusting for sex, diabetes, smoking and low-density lipoprotein cholesterol. The median follow-up period was 8.3 years (interquartile range: 5.3-9.0 years). There were 245 (27%) all-cause deaths including 114 (13%) CV deaths during the follow-up period. MACE occurred in 442 (50%) subjects, but coronary artery interventions (percutaneous coronary intervention or coronary artery bypass grafting) were performed in 578 subjects (65%). A Cox proportional regression analysis confirmed the relationship between PP dipping as well as PP dipping thresholds points and risk of MACE and total mortality only in the group of the oldest subjects. In contrast to younger CAD patients, PP dipping is related to MACE, CV and total mortality in very elderly CAD subjects. Nocturnal PP values tend to be higher than diurnal PP values in the oldest CAD individuals. In conclusion, in contrast to younger CAD patients, PP dipping is related to MACE, CV and total mortality in very elderly CAD subjects. Nocturnal PP values tend to be higher than diurnal PP values in the oldest CAD individuals.


The role of PAX2 in normal and abnormal development of the urinary tract.
The molecular etiology of many urinary tract abnormalities in children remains unknown, but a number of genes with a key role in urogenital development have now been identified. PAX2, one such gene, encodes a transcription factor which is critically required for epithelial differentiation within the urogenital tract. Recent studies suggest that PAX2 mutations lead to urological abnormalities and renal failure, while overexpression of PAX2 in the kidneys of mice causes multifocal microcystic tubular dilatation. In humans persistent PAX2 expression has been identified in multicystic dysplastic kidneys. In this review, recent research on the developmental gene, PAX2, and its involvement in normal and abnormal kidney development is summarized. In addition, an overview of the phenotypes associated with either loss-of-function PAX2 mutations or PAX2 overexpression is presented. A brief summary of factors that are known to regulate PAX2 and genes that may be regulated by PAX2 protein is also included.


Two cases of late-onset cardiovascular toxicities after a single injection of local anesthetics during supraclavicular brachial plexus block - A report of two cases.
Local anesthetics systemic toxicity (LAST) is a grave complication of regional anesthesia that usually occurs immediately after local anesthetics injection. Here, we report on rare late-onset toxicity cases after supraclavicular brachial plexus blocks. Two patients underwent surgery for radius fractures. We used lidocaine 100 mg and ropivacaine 150 mg for blocking and infused dexmedetomidine for intraoperative sedation. The 63-year-old male patient's blood pressure dropped to 87/60 mmHg after 3 h 15 min after blocking. Ventricular fibrillation occurred 10 min later. After five defibrillations, electrocardiography showed ventricular tachycardia that was normalized through one cardioversion. The 54-year-old female patient's heart rate decreased to 35 beats/min 2 h 30 min after blocking. Her vital signs returned to normal after administering atropine, ephedrine, epinephrine, and lipid emulsion. Physicians should remember that LAST may occur long after local anesthetic injection and be aware of factors that may adversely affect the course of LAST.


Human-companion animal relationships and animal behavior problems.
The compatibility of the social systems of humans and companion animals has facilitated the formation of a unique interspecific relationship. Some of the most common behavior problems that people have with their pets are a result of the type of relationship that has formed between them. In most cases, neither pet nor owner is exhibiting abnormal behavior; rather, they are demonstrating normal species-typical behaviors that are unacceptable to the other species.


Positive correlation between cognitive impairment and renal microangiopathy in patients with type 2 diabetic nephropathy: a multicenter retrospective study.
This study was performed to explore the correlation between cognitive impairment and renal microangiopathy in patients with type 2 diabetic nephropathy (T2DN) by detecting changes in cognitive function and cerebral metabolism in these patients with different stages of T2DN. Prospectively maintained databases were reviewed from 2006 to 2017. Blood biochemical indexes and the urinary albumin excretion rate (UAER) were measured in all participants. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MoCA). Cognitive impairment was the primary endpoint. Renal microangiopathy was the secondary endpoint. Pearson correlation analysis was used to assess correlations. Two hundred sixteen patients with type 2 diabetes mellitus (T2DM) were divided into three groups according to their UAER: T2DM without nephropathy (n=72), early T2DM with nephropathy (n=74), and the clinical stage of early T2DM with nephropathy (n=70). Healthy participants were selected as the normal control group (n=70). Pearson correlation analysis demonstrated that the total MMSE and MoCA score was negatively correlated with the UAER (r=-0.327) and positively correlated with the estimated glomerular filtration rate (r=0.428) in patients with T2DN. The present study showed a positive correlation between cognitive impairment and renal microangiopathy in patients with T2DN.


Do optical aberrations contribute to visual loss in strabismic amblyopia?
If aberrations contribute significantly to the decreased visual function of strabismic amblyopic eyes, one would predict that (1) the pupil size for optimum resolution should be smaller in the amblyopic than in the normal eyes, (2) increasing target contrast by a constant ratio should not compensate for defocus of an amblyopic eye, and (3) the contrast sensitivity of the amblyopic eye should improve when tested with a stimulus that bypasses the eye's optics. We tested these predictions, using contrast sensitivity techniques, and found no evidence that aberrations contribute to the amblyope's abnormality.


Fast synthesis of ultra-thin ZnSnO3 nanorods with high ethanol sensing properties.
Ultra-thin 3 nm ZnSnO(3) nanorods were successfully prepared, which not only exhibit high sensitivity to ethanol at relatively low temperature, but also good selectivity.


Child mental health consultation with families of medically compromised infants.
Prematurity and birth defects present parents with a crisis for which they have usually had little preparation and no prior education. Both types of early medical complications may represent a state of suspended animation for most parents. Even large premature infants with good prognoses induce anxiety and symbolize potential death and disability, and children with birth defects may portend years of medical procedures and long-term disability. The fear of serious neurologic impairment or mental retardation presents parents with a long period of ambiguity and chronic anxiety. During this period, they must be helpless observers rather than active participants. Recent research has indicated that the active involvement of parents in the care of their premature infants can be helpful in alleviating the guilt and anxiety related to loss and impairment. Similarly, early physical contact between parents and their severely malformed infant is equally critical. Even if the ultimate complexities of early attachment have yet to be delineated fully, this is a worthwhile practice and useful approach in the nursery. Child mental health professionals have important roles to fulfill in helping staff members deal with increased parental participation and directly managing family members with intense distress related to their infants' fragility. The role of the mental health professional in such consultation may cover five related tasks: 1. Understanding the nature of the biologic issues facing the child and integrating that understanding with an evaluation of the child's neurobehavioral profile. 2. Understanding the family's relationship with the child and their overall level of functioning during an acutely stressful time. 3. Developing an appreciation of the place of the child in his or her family and how the parents understand the nature of the medical problems. 4. Forming a collaborative relationship with the pediatricians and other subspecialists who care for the child so that behavioral and psychological interventions are integrated with the child's biomedical care. 5. Fostering a brief, or sometimes long-term, therapeutic relationship with the family or facilitating the family's finding such a relationship with another clinician. There will never be enough child and adolescent psychiatrists and psychologists to treat all families of medically compromised infants. Knowledge of normative responses has advanced to the point at which basic skills can be used by and transmitted to others who can provide basic services. There is much to be learned about the short- and long-term sequelae of such stressful situations on individuals and family systems with preexisting psychopathology. For such families, child mental health professionals are uniquely suited to play a further role in research and treatment.


The virtually mature B-type natriuretic peptide (BNP1-32) is a precursor for the more effective BNP1-30.
The B-type natriuretic peptide (BNP1-32) exerts vasorelaxing and cardioprotective activity. BNP is used as a biomarker for the diagnosis of cardiopathological conditions and recombinant BNP1-32 as a drug for the treatment of such. BNP1-32 has a short half-life and thus, similar to other vasoactive peptides like angiotensin II and bradykinin, can be enzymatically truncated forming bioactive metabolites. We aimed to investigate the metabolism of BNP1-32 in the mouse lung, to identify potential new BNP metabolites and to disclose their biological activity compared to the BNP1-32, in vitro and in vivo. Using HPLC and MS, we identified a new BNP metabolite, BNP1-30, in the lung being generated by endothelin-converting enzyme-1. BNP1-30 is more efficient in stimulating the guanylyl cyclase (GC) receptor A and, in contrast to BNP1-32, is also able to profoundly stimulate the GC-B. In vivo, BNP1-30 reduced the mean arterial BP of normotensive mice after acute infusion significantly more than BNP1-32. In a model of severe hypertension, a 3-day infusion of BNP1-30 was able to reduce systolic BP by 30 mmHg and to improve markers of heart failure, while BNP1-32 was without significant effect. Our results suggest that BNP1-32 is the precursor for the biologically more active BNP1-30 leading to a fundamental extension of the natriuretic peptide system. Due to expanded activity, BNP1-30 might be a promising treatment option for cardiovascular diseases. Furthermore, its potency as a new diagnostic marker of specific cardiac diseases should be evaluated.


A new spacer group derived from arylmalonaldehydes for glucuronylated prodrugs.
A new glucuronylated prodrug of doxorubicin, potentially useful for ADEPT or PMT cancer chemotherapy, has been prepared from 4-methyl phenyl malonaldehyde. The enol ether spacer, linked via a carbamate to the 3'-amino group of doxorubicin is rapidly cleaved after beta-glucuronidase (E coli) catalyzed hydrolysis at pH 7.2 and 37 degrees C.


Aggressive fibromatosis (extra-abdominal desmoids) of the head and neck.
Five cases of aggressive fibromatosis of the head and neck area (extra-abdominal desmoids) are presented. The clinical and histological character of local aggressiveness of these tumours is emphasised. Radical surgery, when feasible, is the only satisfactory form of treatment. Excision of as much tumour tissue as preservation of vital structures in the area will permit can also offer worthwhile palliation.


Comparison of EBV-infectivity measured by EBNA-induction and immortalization of human B-cells.
Epstein-Barr virus (EBV) infectivity was measured by two different systems. One was EBV-specific antigen (EBNA) induction in EBV-negative BJAB cells, the other was immortalization of human peripheral blood B-lymphocytes upon EBV infection. Because the sensitivity of the EBNA-induction assay, which takes 2-3 days, was similar with that of B-cell immortalization, which takes 6-8 weeks, the former can be used for the rapid and convenient determination of EBV-infectivity.


Increased density of excitatory amino acid transport sites in the hippocampal formation following an entorhinal lesion.
High affinity transport of excitatory amino acids such as L-glutamate into astrocytes is necessary for the termination of its excitatory signal and the prevention of its excitotoxic effects. The removal of glutamate from the synaptic cleft is carried out by both sodium- and chloride-dependent systems. Both sodium-dependent D-[3H]aspartate and chloride-dependent L-[3H]glutamate binding were found to increase in the dentate gyrus molecular layer of rats following an entorhinal lesion. The increased binding reached a maximum at 5 and 7 days postlesion and returned to normal by 12 days postlesion. No changes in binding were observed at long time points postlesion. This increased ability to transport glutamate may be a compensatory response to protect the remaining neurons from the excitotoxic conditions that accompany neuronal degeneration.


A 5-year propensity-matched analysis of perioperative outcomes in patients with chronic kidney disease undergoing bariatric surgery.
Bariatric surgery can improve renal function in patients with comorbid chronic kidney disease (CKD) and obesity. Additionally, bariatric surgery can enhance outcomes following renal transplantation. The safety of bariatric surgery in patients with CKD has been debated in the literature. This study evaluates the frequency of perioperative complications associated with CKD. The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database was queried from 2015-2019. Patients were included if they had a vertical sleeve gastrectomy (VSG) or Roux-en-Y gastric bypass (RYGB) and were stratified based on CKD status. An unmatched and propensity-matched analysis was performed comparing 30-day perioperative outcomes between the groups. A total of 717,809 patients included in this study, 5817(0.8%) had CKD, of whom 2266(0.3%) were on dialysis. 74.3% of patients with CKD underwent VSG with 25.7% underwent RYGB. Comparing RYGB to VSG, patients who underwent RYGB had a higher rate of deep organ space infection (0.7%vs.0.1%,p = 0.021) and re-intervention (5.0% vs. 2.2%,p < 0.001). Within the VSG cohort, a matched analysis was performed for those with CKD and without CKD. The CKD cohort had higher risk of complications such as bleeding (2.1%vs. 0.9%,p < 0.001), readmission (9.3%vs.4.9%,p < 0.001), reoperation (2.7%vs.1.3%,p < 0.001), and need for reintervention (2.2%vs.1.3%,p < 0.001). Notably, patients with CKD also had a higher mortality (0.6%vs.0.2%,p = 0.003). No difference was seen between patients with renal insufficiency and patients on dialysis. VSG has been the operation of choice in patients with CKD. Our results showed it is the safer option for patients with CKD compared to RYGB. Although this patient population does have an increased risk of adverse perioperative events, dialysis didn't affect the outcome. Bariatric surgeons who operate on patients with CKD should be well informed and remain vigilant given the increased perioperative risk. The risk is still considerably low, and the potential benefit on renal function and improvement in candidacy for renal transplant outweigh the risk. They should be considered as surgical candidates.


Modulatory effect of amifostine (WR-1065) against genotoxicity and oxidative stress induced by methotrexate in human umbilical vein endothelial cells (HUVECs).
Amifostine is used in chemotherapy and radiotherapy as a cytoprotective adjuvant alongside DNA-binding chemotherapeutic agents. It functions by reducing free radicals and detoxifying harmful metabolites. Methotrexate, as an antimetabolite drug has been considered for treating various cancers and autoimmune diseases. However, the cytotoxic effects of methotrexate extend beyond tumor cells to crucial organs, including the heart. This study applied the HUVEC cell line as a reference in vitro model for researching the characteristics of vascular endothelium and cardiotoxicity. The current study aimed to assess amifostine's potential cytoprotective properties against methotrexate-induced cellular damage. Cytotoxicity was measured using the MTT assay. Apoptotic rates were evaluated by Annexin V-FITC/PI staining via flow cytometry. The genoprotective effect of amifostine was determined using the comet assay. Cells were exposed to various amifostine doses (10-200 μg/mL) and methotrexate (2.5 μM) in pretreatment culture condition. Methotrexate at 2.5 μM revealed cytotoxicity, apoptosis, oxidative stress and genotoxicity while highlighting amifostine's cyto/geno protective properties on HUVECs. Amifostine significantly decreased the levels of ROS and LPO while preserving the status of GSH and SOD activity. Furthermore, it inhibited genotoxicity (tail length, %DNA in tail, and tail moment) in the comet assay. Amifostine markedly attenuated methotrexate-induced apoptotic cell death (early and late apoptotic rates). These findings convey that amifostine can operate as a cytoprotectant agent.


Lack of functionally active Melan-A(26-35)-specific T cells in the blood of HLA-A2+ vitiligo patients.
Vitiligo, a skin disorder characterized by the spontaneous destruction of melanocytes, is believed to be of autoimmune origin. We investigated the presence and functionality of CD8(+) T-cells specific for the melanocyte-associated antigens Melan-A, gp100, tyrosinase, and TRP-2 in the blood of HLA-A2(+) vitiligo patients. We enumerated antigen-specific CD8(+) T cells by major histocompatibility complex multimer staining directly ex vivo, as well as after 9 days of in vitro stimulation and assessed IFN-gamma secretion by enzyme-linked immunospot (Elispot) assay. Tyrosinase-, gp100-, or TRP-2-specific CD8(+) T cells could not be identified in the peripheral blood of individuals with vitiligo. Although Melan-A-specific T cells were detectable at levels comparable to Flu-MP-specific T cells by multimer staining, these lymphocytes did not express the skin-homing receptor cutaneous lymphocyte antigen, were phenotypically naïve (CD45RA(+)), and were unresponsive in the IFN-gamma Elispot assay, suggesting that they are unlikely to be involved in the etiopathogenesis of vitiligo.


Minor psychiatric disorders and objective diagnosis of gastroesophageal reflux disease.
Symptoms may be unreliable to diagnose gastroesophageal reflux disease (GERD) in patients with minor psychiatric disorders (MPD). This study aims to evaluate the influence of MPD in the diagnosis of GERD. We prospectively studied 245 patients (based on a sample size calculation) with suspected GERD. All patients underwent manometry and pH monitoring and MPD evaluation based on the Hospital Anxiety and Depression Scale (HADS). Based on the results of the pH monitoring, patients were classified as GERD + (n = 136, 55% of the total, mean age 46 years, 47% females) or GERD - (n = 109, 45% of the total, mean age 43 years, 60% females). The mean HADS score for GERD + and GERD - for anxiety was 7.8 and 8.5, respectively (p = 0.8) and for depression was 5.4 and 6.1, respectively (p = 0.1). DeMeester score (DS) did not correlate with total HADS score (p = 0.08) or depression domain (p = 0.9) but there was a negative correlation between DS and anxiety level (p < 0.001). A significant threshold accuracy value for HADS to diagnose GERD was not found on receiver operating characteristics curve analysis. Almost half of the patients evaluated for GERD did not have the disease on objective evaluation. GERD + and GERD - patients had similar levels of MPD. However, the amount of reflux correlated negatively with the severity of anxiety. Symptoms and HADS cannot accurately diagnose or exclude GERD. pH monitoring should be more liberally used especially in patients with high levels of anxiety.


Echo dephasing and heat capacity from constrained and unconstrained dynamics of triiodothyronine nuclear receptor protein.
The objective of this study is to observe the echo feature curves, vibrational dephasing, and heat capacity of a protein-hormone system taking thyroid hormone receptor-beta (THR-β) as an example. Constrained and unconstrained molecular dynamics simulations are performed by implementing the theory of velocity reassignments to probe the phase coherent state in terms of echo pulses. The constrained vibrations are incorporated by adjusting rigid bonds to all hydrogen atoms with an integrator parameter of 2 fs/step in order to reduce the degrees of freedom whereas 1 fs/step is used in the free vibrations of the atomic cluster. The nature of temperature auto-correlation functions changes so that echo feature curves also show a distinct nature in the cases of constrained and unconstrained vibrations. There is a large variation in kinetic temperature and internal potential energy in the echo time zone. The temperature rate of change of internal potential energy is the main contributor to the heat capacity of the native state protein-hormone system. The heat capacity of proteins estimated from this technique is in good agreement with the values from experiments. This study shows that triiodothyronine (T3) hormone makes some differences in heat capacity upon binding to the THR-β ligand binding domain (LBD). The physical properties of unliganded THR-β and T3-bound THR-β LBD in the cases of constrained and unconstrained dynamics are observed distinctly under the effect of anharmonicity on the phase coherent state of normal modes and the dephasing time lies in a range of 0.6-0.8 ps when the systems are perturbed suddenly.


[Myocardial metabolism under intravenous infusion of glucagon (author's transl)].
In 7 healthy-hearted probands the arterial-coronary-venous oxygen difference for glucose, K+, lactate, pO2, pCO2 and pH during a glucagon infusion was determined and compared with the values before and 10 minutes after infusion. Contradictory to the unchanged myocardial lactate extraction and the positively or negatively influenced K+-uptake recorded in the literature, in this contingent there was a statistically significant myocardial lactate production and an unchanged potassium uptake. The respiratory quotient of the heart increased. These changes are regarded as the result of a direct hormonal influence on the myocardial metabolism and have nothing to do with the change of an aerobic into an anaerobic metabolic state.


[Pilon tibiale fractures].
In the AO classification, the distal tibia is 43 and A type injuries are extra-articular, B type partial articular and C type involve the whole of the articular surface with complete separation of the joint from the diaphysis. The term pilon fracture should be confined to B(3) and C type fractures. The injury mechanism of pilon fractures will vary from a simple fall to a high energy road traffic accident, leading to increasing fracture comminution and greater soft tissue injury with more open fractures. Plain radiographs and CT-scans are diagnostic prerequisites. A spanning external fixator, with or without fixing the fibula, is the initial method of choice. The goal is to span the zone of injury with the fixator, to align the limb, to reduce the articular surface through very limited approaches, and to minimize complications related to treatment to maintain length and provisionally align the fracture. When soft tissue swelling has subsided definitive stabilization is performed. Bone grafting of defects is rarely necessary.


Different metal-decorated aluminum phosphide nanotubes as hydrazine sensors for biomedical applications.
B3LYP, B97D, and M06-2X density functionals are utilized for probing the effect of decorating X (X = Co, Ti, Sc, or Ca) metals on the sensing performance of an aluminum phosphide nanotube (AlPNT) in detecting the hydrazine (HZ) gas. We predict that the interaction of pristine AlPNT with HZ is physisorption, and our calculated sensing response (SR) of AlPNT is approximately 2.7. The adsorption energy of HZ changes from - 4.6 to - 21.0, - 21.9, - 22.4, and - 23.8 kcal/mol by decorating the Co, Ti, Sc, and Ca metals into the AlPNT surface, respectively. Also, Co, Ti, Sc, and Ca rise the SR to 22.5, 36.8, 50.4, and 89.0, respectively, indicating that by increasing the atomic radius of metals, the sensitivity is more increased. So, we concluded that Ca much more increases the sensitivity of AlPNT toward HZ. Our calculations demonstrate that the electrostatic interaction has the main contribution in the formation of HZ/X decorated AlPNT (X@AlPNT) complexes. The expected recovery time is 22.0 s for the HZ desorption from the Ca@AlPNT at 298 K. Finally, we found that all of the X@AlPNTs have superior sensing performance toward HZ compared to the X@carbon nanotubes.


Investigation of herb-drug interactions with ginkgo biloba in women receiving hormonal treatment for early breast cancer.
Women receiving treatment for breast cancer commonly ingest herbal medicines. Little is known about the potential for herb-drug interactions in this population. The aim of this study is to investigate the effect of ginkgo biloba co-administration on the pharmacokinetics of tamoxifen, anastrozole and letrozole. This was a prospective open-label cross-over study in 60 women with early stage breast cancer taking either tamoxifen, anastrozole or letrozole (n=20/group). Participants received ginkgo biloba (EGb 761) for 3 weeks (120 mg twice daily). Trough concentrations of drugs were measured before and after ginkgo biloba treatment using LC-MS/MS. Toxicities were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events. Trough concentrations before and after treatment with ginkgo biloba were not significantly different for tamoxifen (93.5 ± 29.0, 86.5 ± 25.3 ng/mL; p=0.16), letrozole (91.1 ± 50.4, 89.6 ± 52.14 ng/mL; p=0.60) or anastrozole (29.1 ± 8.6, 29.1 ± 7.6 ng/mL; p=0.97). Ginkgo biloba was well tolerated, with no difference in toxicity during ginkgo biloba. Co-administration of ginkgo biloba does not significantly affect the pharmacokinetics of tamoxifen, anastrozole or letrozole. There was no difference in the toxicity profile of hormone therapy with ginkgo biloba use in women with early stage breast cancer.


Diversity and community ecology of forest epiphyte testate amoebae from European Russia.
Testate amoebae are an abundant group of microorganisms which make a significant contribution to the diversity of protist life. Most of the world's potential habitats for testate amoebae have been barely studied and when such places are investigated they frequently reveal novel communities and species. Here we consider the testate amoeba communities associated with boreal forest epiphytes (mosses and lichens); an environment which we argue has been under-researched. We present a dataset of 165 samples from four regions of western Russia and analyse these data in relation to micro-habitat position and selected environmental data. The testate amoebae of epiphytes are abundant but dominated by ubiquitous species. We show that there are trends toward a lower species richness and test concentration with greater elevation on the trunk and in lichens compared to mosses. There are considerable differences in community composition between sampling regions. Of all measured environmental variables only moisture content showed a significant relationship with testate amoeba community structure. Our data highlight how little is known about testate amoeba communities of this habitat and call for greater research efforts, particularly in less-studied regions and biomes.


Current understanding of CREPT and p15RS, carboxy-terminal domain (CTD)-interacting proteins, in human cancers.
CREPT and p15RS, also named RPRD1B and RPRD1A, are RPRD (regulation of nuclear pre-mRNA-domain-containing) proteins containing C-terminal domain (CTD)-interacting domain (CID), which mediates the binding to the CTD of Rpb1, the largest subunit of RNA polymerase II (RNAPII). CREPT and p15RS are highly conserved, with a common yeast orthologue Rtt103. Intriguingly, human CREPT and p15RS possess opposite functions in the regulation of cell proliferation and tumorigenesis. While p15RS inhibits cell proliferation, CREPT promotes cell cycle and tumor growth. Aberrant expression of both CREPT and p15RS was found in numerous types of cancers. At the molecular level, both CREPT and p15RS were reported to regulate gene transcription by interacting with RNAPII. However, CREPT also exerts a key function in the processes linked to DNA damage repairs. In this review, we summarized the recent studies regarding the biological roles of CREPT and p15RS, as well as the molecular mechanisms underlying their activities. Fully revealing the mechanisms of CREPT and p15RS functions will not only provide new insights into understanding gene transcription and maintenance of DNA stability in tumors, but also promote new approach development for tumor diagnosis and therapy.


Neuroimaging observations linking neurocysticercosis and mesial temporal lobe epilepsy with hippocampal sclerosis.
To test if chronic calcificed neurocysticercosis (cNCC) and hippocampal sclerosis occur more often than by chance ipsilateral to the same brain hemisphere or brain region in mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) plus neurocysticercosis. This proof-of-concept would provide important evidence of a direct pathogenic relationship between neurocysticercosis and MTLE-HS. A cohort of 290 consecutive MTLE-HS surgical patients was studied. A test of proportions was used to analyze if the proportion of patients with a single cNCC lesion matching the same brain hemisphere or region of hippocampal sclerosis was significantly greater than 50%, as expected by the chance. Neuroimaging findings of cNCC were observed in 112 (38.6%) of 290 MTLE-HS patients and a single cNCC lesion occurred in 58 (51.8%) of them. There were no differences in main basal clinical characteristics of MTLE-HS patients with single or multiple cNCC lesions. In patients with single cNCC lesions, the lesion matched the side in which hippocampal sclerosis was observed in 43 (74.1%) patients, a proportion significantly greater than that expected to occur by chance (p=0.008). Neurocysticercosis in temporal lobe was ipsilateral to hippocampal sclerosis in 85.0% of patients and accounted mostly for this result. This work is a proof-of-concept that the association of neurocysticercosis and MTLE-HS cannot be explained exclusively by patients sharing common biological or socio-economic predisposing variables. Instead, our results suggest the involvement of more direct pathogenic mechanisms like regional inflammation, repetitive seizures or both. Neurocysticercosis within temporal lobes was particularly related with ipsilateral hippocampal sclerosis in MTLE-HS, a finding adding new contributions for understanding MTLE-HS plus cNCC or perhaps to other forms of dual pathology in MTLE-HS.


A separable convolutional neural network-based fast recognition method for AR-P300.
Augmented reality-based brain-computer interface (AR-BCI) has a low signal-to-noise ratio (SNR) and high real-time requirements. Classical machine learning algorithms that improve the recognition accuracy through multiple averaging significantly affect the information transfer rate (ITR) of the AR-SSVEP system. In this study, a fast recognition method based on a separable convolutional neural network (SepCNN) was developed for an AR-based P300 component (AR-P300). SepCNN achieved single extraction of AR-P300 features and improved the recognition speed. A nine-target AR-P300 single-stimulus paradigm was designed to be administered with AR holographic glasses to verify the effectiveness of SepCNN. Compared with four classical algorithms, SepCNN significantly improved the average target recognition accuracy (81.1%) and information transmission rate (57.90 bits/min) of AR-P300 single extraction. SepCNN with single extraction also attained better results than classical algorithms with multiple averaging.


The T- and L-type calcium channel blocker (CCB) mibefradil attenuates leg edema induced by the L-type CCB nifedipine in the spontaneously hypertensive rat: a novel differentiating assay.
Among the L-type calcium channel blockers (CCBs), particularly dihydropyridines like nifedipine [1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester], a common adverse effect is vasodilatory edema. Newer CCBs, such as the T- and L-type CCB, mibefradil [(1S,2S)-2-[2[[3-(2-benzimidazolylpropyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride hydrate], demonstrate antihypertensive efficacy similar to that of their predecessors but seem to have a reduced propensity to cause edema. Using a magnetic resonance imaging (MRI) T(2) mapping technique, we investigated the ability of mibefradil to reduce extracellular water accumulation caused by the L-type CCB, nifedipine, in the hindleg skeletal muscle of the spontaneously hypertensive rat. Mibefradil (10 mg/kg i.v.) and nifedipine (1 mg/kg i.v.) lowered mean arterial blood pressure by 97 +/- 5 and 77 +/- 4 mm Hg, respectively. MRI edema index (expressed as percentage increase of integral T(2) over predrug control) was significantly higher with nifedipine (2606 +/- 86%; p < 0.05) than with mibefradil (981 +/- 171%) measured 30 to 60 min after the start of drug infusion. The hindleg edema caused by nifedipine was dose dependently decreased by coadministration of mibefradil (0, 0.3, or 3 mg/kg). The hindleg edema formation was not due to albumin leakage into the interstitial space based on immunostaining. However, a 4.2-fold increase in the arterial L-/T-type CC mRNA expression ratio was observed compared with the venous L/T ratio as shown by quantitative reverse transcription polymerase chain reaction. These results demonstrate the novel utility of MRI to measure extravascular water after acute exposure to CCBs and indicate that T-type CCB activity may reduce L-type CCB-induced vasodilatory edema in the skeletal muscle vasculature, possibly by a differential effect on arteriole and venule dilatation.


The "plain film" bladder shadow in outflow obstruction: as accurate a discriminant of residual urine as ultrasound.
The height, width and area of the bladder shadow on post-micturition plain abdominal radiography was compared with the residual urine obtained at endoscopy from 58 men presenting with pure bladder outflow obstruction. Each parameter of the bladder shadow correlated significantly with the residual urine in patients in whom this shadow was visible. Post-micturition plain abdominal radiography is considerably cheaper than ultrasound and appears to be equally effective in the determination of residual urine. Its use as the sole imaging technique in the routine management of bladder outflow obstruction is recommended.


Microsatellite markers for Grosmannia alacris (Ophiostomataceae, Ascomycota) and other species in the G. serpens complex.
Polymorphic microsatellite markers were developed for the pine-infecting fungus, Grosmannia alacris. Sixteen microsatellite markers were developed by using inter-simple sequence repeat (ISSR)-PCRs and 454 sequencing methods. Seven of these markers showed polymorphisms for a South African population of G. alacris, and 13 markers showed polymorphism when European isolates were included. Most of the primer pairs also amplified four closely related species: G. serpens, Leptographium gibbsii, L. castellanum, and L. yamaokae. These new markers will be useful for population studies of G. alacris and other species in the G. serpens complex.


Parental Satisfaction with Pediatric Day-Care Surgery and its Determinants in a Tertiary Care Hospital.
The objective is to assess the level of parental satisfaction of pediatric day-care surgery and its different determinants. This is a descriptive study performed in a tertiary care hospital in India among parents of pediatric day-care surgery patients from June 2013 to March 2015. The core questionnaire for the assessment of patient satisfaction for general day care (COPS-D) was used. Variables related to surgery, overall satisfaction, one open-ended question, and socio-demographic data were also collected. Calculated sample size was 121. The mean and standard deviation of parental satisfaction were estimated in eight domains of day care (COPS-D) using Likert scale 1-5. Preadmission visit had a mean of 4.63 (0.52), day of surgery 4.65 (0.58), operating room 4.76 (0.51), nursing care 4.46 (0.79), medical care 4.89 (0.48), information 4.51 (0.68), autonomy 4.64 (0.56), and discharge 4.50 (0.72). In elder children, there was less satisfaction on the information and discharge domains. Overall satisfaction was good in 88% of patients and was less than satisfactory when they had significant pain. Perception of quality of pediatric day-care surgery was assessed with a questionnaire and was found to be good. Variables related to surgery such as pain may be included in the questionnaire for assessing satisfaction in the day-care surgery.


Different subtypes of collateral vessels in hemorrhagic moyamoya disease with p.R4810K variant.
The aim of this study was to investigate the hemorrhgic sites and collateral vessels in hemorrhagic MMD with the p.R4810K variant. Hemorrhage sites were classified as either anterior or posterior. Collateral vessels were classified into three subtypes according to origin: lenticulostriate anastomosis, thalamic anastomosis, and choroidal anastomosis. Hemorrhage sites and collateral vessels were compared between patients with wild-type p.R4810K variant (GG) and patients with heterozygous p.R4810K variant (GA) after 1:1 propensity score matching. A total of 130 hemorrhagic MMD patients were included in present study, 21 pairs (42 hemorrhagic hemispheres) were obtained after 1:1 propensity score. In GA group, 16 hemispheres (76.2%) presented anterior hemorrhage, and 5 hemispheres (23.8%) presented with posterior hemorrhage. In GG group, 13 hemispheres (61.9%) presented anterior hemorrhage, and 8 hemispheres (38.1%) presented with posterior hemorrhage. No significant differences were found in hemorrhagic sites between two matched groups (P > 0.05). Of 21 hemispheres in GA group, 10 (47.6%) exhibited lenticulostriate anastomosis, 6 (28.6%) thalamic anastomosis, and 6 (28.6%) choroidal anastomosis. Of 21 hemispheres in GG group, 3 (14.3%) exhibited lenticulostriate anastomosis, 5 (23.8%) thalamic anastomosis, and 9 (42.9%) choroidal anastomosis. There was significant difference in lenticulostriate anastomosis between two matched groups (P = 0.045). After adjustment the age, sex, and PCA involvement, we found that lenticulostriate anastomosis was associated with p.R4810K variant (OR, 5.995; 95% CI, 1.296-27.737; P = 0.022). Lenticulostriate anastomosis might be associated with p.R4810K variant. Whereas hemorrhagic sites, thalamic anastomosis, and choroidal anastomosis might not be associted withp.R4810K variant.


[Expression of receptor activator nuclear factor kappa B ligand and osteoprotegerin in peri-implant soft tissue and bone tissue].
To study mRNA expression of receptor activator nuclear factor kappa B ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG) in peri-implant tissue during unloading period. An animal model of dental implant was established in 6 male Beagle dogs of 1-2 years old. Bone remodeling was tested at 3, 7, 15, 30, 60 and 90 days since the placement of implants. RANKL and OPG mRNA expression were quantified by real-time polymerase chain reaction (PCR). Then mandibular bones were taken out and the morphological changes were observed by X-ray, bone tissue was tested by immunohistochemistry stain. The most prominent period of bone remodeling occurred at 7th day after the placement of implants. The expression of RANKL and OPG increased in a time-dependent manner in both soft and hard tissue. After 7 days they gradually decreased. RANKL and OPG can express in soft tissue, and the changing tendency is consistent with the change of bone remodeling, it indicates that RANKL and OPG play an important role in the bone remodeling.


A correlative light-, fluorescence- and electron-microscopic study of neuroepithelial bodies in the lung of the red-eared turtle, Pseudemys scripta elegans.
Neuroepithelial bodies (NEB) were identified for the first time in the respiratory tract of a reptile by the use of combined morphological and histochemical methods. In the red-eared turtle, Pseudemys scripta elegans, NEB were found within the trabecular epithelium of the respiratory tract, mainly in the branching regions of the trabeculae. An intracellular formaldehyde-induced fluorescent compound was identified as 5-hydroxytryptamine (5-HT) by means of microspectrofluorometry. Subsequent histochemical staining of the same fluorescent sections showed the 5-HT-containing cells to be argentaffin. In electron micrographs cell clusters characterized by the presence of distinctive cytoplasmic, membrane-bounded dense granules (+/- 100 nm) were observed, correlating with the distribution of the yellow-fluorescent epithelial cells. The granules of the NEB are positive when the argentaffin technique is performed directly on ultrathin sections. Cells of the NEB extend into the lumen of the airway via apical microvilli and a single modified cilium displaying a 9 X 2 + 0 or 8 X 2 + 2 microtubular pattern. Unmyelinated axons containing mostly small, clear vesicles were seen in close association with NEB cells, often forming synaptic junctions. Occasionally, axons containing a few small dense-cored vesicles were found. The relationship between NEB cells and capillaries, the images of emiocytotic granule release and the occurrence of synaptic contacts between axons and granule-containing cells are indicative of endocrine secretion. These features and the presence of intracytoplasmic granules containing 5-HT may justify the inclusion of NEB-cells of the turtle lung into the diffuse neuroendocrine system. Furthermore, structurally these cells appear to represent sensory elements capable of an intrapulmonary receptor-secretory function.


Impact of Early Mobilization in the Intensive Care Unit on Psychological Issues.
Early mobilization is an intervention protocol that can be employed in the critically ill population to effectively reduce the risks and consequences normally associated with immobility in high-acuity patients. In turn, rate and quality of recovery are improved as well as overall patient outcomes. Although there are many challenges inherent to the implementation of an early mobilization program, success of such a program is achievable through structured education of staff and diligence in its application. As a result, staff and patient experience the benefits of medical treatment that addresses a patient's immediate needs without ignoring that treatment's long-term effect.


An economic evaluation of the expanded food and nutrition education program.
To evaluate the New York State Expanded Food and Nutrition Education Program using economic methodology. Data were collected by nutrition educators in a pretest, posttest design with an epidemiological modeling approach to assess costs and estimate potential health benefits of the state program. Cooperative Extension, 35 counties. 5730 low-income participants. Series of 6 or more food and nutrition lessons. Cost (program and participant); health benefits in quality adjusted life years (QALYs); and monetized benefits: society's willingness to pay for QALYs, and benefits of avoiding or delaying health care costs and loss of productivity. Cost-effectiveness estimated from behavior change and QALY weights. Cost-benefit ratios estimated from costs and monetized benefits. Sensitivity analyses provided ranges where lack of agreement exists around parameters' values. Cost was $892/graduate. Cost-effectiveness was 245 QALYs saved, at $20863/QALY (sensitivity 42-935 QALYs, $5467-$130311 per QALY). Societal willingness to pay benefit-to-cost ratio was $9.58:$1.00 (sensitivity $1.44-$41.92:$1:00); narrow governmental benefit-to-cost ratio was $0.82:$1.00 (sensitivity $0.08-$4.33:$1:00). Outcome data indicate that food and nutrition behavior changes resulting from the Program are likely to improve future health and reduce health care costs. Cost-effectiveness is estimated to be as great as for many current health interventions.


Silencing of Hsp70 intensifies 6-OHDA-induced apoptosis and Hsp90 upregulation in PC12 cells.
By the current study, we tried to find out the interactive mechanisms enrolled by Hsp70 and Hsp90 following the 6-hydroxydopamine (6-OHDA)-induced oxidative stress. Of heat shock protein (Hsp) family, we have previously evaluated the effects of Hsp90 gene silencing on in vitro model of Parkinson's disease and its influence on controlling the mechanisms of cell survival. Here, we extended our study to Hsp70 silencing short interfering RNA (siRNA) oligonucleotides, transfected into Pheochromocytoma (PC12) cells with/without exposure to 6-OHDA stress. In order to determine the probable effects of Hsp70 silencing on apoptotic factors, we assessed Bcl2/Bax ratio, nuclear level of PARP, and cleavage of caspase-3 under 6-OHDA stress condition. The results showed deteriorated effect of Hsp70 siRNA on apoptosis in cells exposed to only 6-OHDA. This is, at least in part, in consequence of upregulation of Hsp90, both at messenger RNA (mRNA) and protein levels. These data highlight the critical role of Hsp70 for cell survival under 6-OHDA stress condition. It could be a suggestive issue for supervision of caspase cascades by survival roles of Hsps as Hsp70 silencing resulted in apoptosis phenomenon. Convergence of Hsp70 anti-apoptotic and 6-OHDA pro-apoptotic pathways may explain intensified apoptosis following Hsp70 silencing. In addition, nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor, has been previously studied in detoxification of oxidative stress. For this issue, we tried to elucidate Hsp70 silencing impact on Nrf2, which has been shown to regulate the transcription of Hsp70, unspecifically. Besides, our investigations revealed that Hsp70 siRNA did not affect the level of Nrf2 during 6-OHDA exposure. But, it is still a dealing question and other investigations are needed to have a comprehensive perception of Hsp family signaling functions.


Partial KCNQ1OT1 hypomethylation: A disguised familial Beckwith-Wiedemann syndrome as a sporadic adrenocortical tumor.
Beckwith-Wiedemann syndrome has a wide spectrum of complications such as embryonal tumors, namely adrenocortical tumor. Tumor predisposition is one of the most challenging manifestations of this syndrome. A 45-day old female with a family history of adrenocortical tumor presented with adrenocortical tumor. The case raised suspicion of a hereditary Beckwith-Wiedemann syndrome, therefore molecular analysis was undertaken. The results revealed partial KCNQ1OT1 hypomethylation in the infant's blood DNA which was associated with a complete loss of methylation in the infant's adrenocortical tumor tissue. It is unique for familial Beckwith-Wiedemann syndrome caused by KCNQ1OT1 partial hypomethylation to manifest solely through adrenocortical tumor. Incomplete penetrance and specific tissue mosaicism could provide explanations to this novel hereditary Beckwith-Wiedemann syndrome presentation.


Chronic Treatment with Naltrexone Prevents Memory Retention Deficits in Rats Poisoned with the Sarin Analog Diisopropylfluorophosphate (DFP) and Treated with Atropine and Pralidoxime.
Humans and rats poisoned with sarin develop chronic neurological disabilities that are not prevented with standardized antidotal therapy. We hypothesized that rats poisoned with the sarin analogue diisopropylfluorophosphate (DFP) and resuscitated with atropine and pralidoxime would have long-term memory deficits that were preventable with naltrexone treatment. Long Evans rats (250-275 g) were randomized to: DFP (N = 8): single subcutaneous (SC) injection of DFP (5 mg/kg). Treatment (N = 9): DFP (5 mg/kg) followed by chronic naltrexone (5 mg/kg/day × 12 weeks). Control (N = 12): single SC injection of isopropyl alcohol, (DFP vehicle) followed by chronic naltrexone (5 mg/kg/day). If toxicity developed after injection, antidotal therapy was initiated with atropine (2 mg/kg) and pralidoxime (25 mg/kg) and repeated as needed. After 12 weeks, rats underwent testing for place learning (acquisition) across 5 days of training using the Morris Water Maze. On day 6 a memory retention test was performed. Statistical analysis was performed using IBM SPSS Statistics. Rats receiving DFP rapidly developed toxicity requiring antidotal rescue. No differences in acquisition were seen between the DFP vs. DFP + naltrexone rats. During memory testing, DFP-poisoned rats spent significantly less time (29.4 ± 2.11 versus 38.5 ± 2.5 s, p < 0.05) and traveled less distance (267 ± 24.6 versus 370 ± 27.5 cm, p < 0.05) in the target quadrant compared to the treatment group. Treatment rats performed as well as control rats (p > 0.05) on the test for memory retention. Poisoning with DFP induced impaired memory retention. Deficits were not prevented by acute rescue with atropine and pralidoxime. Chronic naltrexone treatment led to preserved memory after DFP poisoning.


Maternal diet quality and associations with body composition and diet quality of preschool children: A longitudinal study.
Nutrition, associated with nutritional status, influences the growth of children. This study aimed to identify the association between maternal diet quality and the diet and body composition of their children. This is a prospective longitudinal study with mother-child pairs. To assess diet quality, nutritional status, and socioeconomic data, two interviews in the children's first and third months of life (2011-2016) and one interview when children were of preschool age (2017-2019) were performed. Diet quality was assessed based on daily food consumption and frequency, considering: 1) food groups, based on the Brazilian food pyramid; 2) level of processing, according to the NOVA classification (unprocessed and/or minimally processed foods, processed foods and ultra-processed foods). One-way ANOVA with Tukey post hoc and Kruskal-Wallis with Dunn's post hoc tests were used to evaluate the influence of factors on children's diet quality. Pearson and Spearman's correlations were used to evaluate the relationship between maternal and children's diet quality, maternal schooling level, and child age. Along with the nutritional assessment of children, multiple linear regression models assessed the impact of covariables on maternal and children's diet quality. Eighty-three mother-child pairs participated in this study. The more frequent the maternal consumption of unprocessed and/or minimally processed foods, the higher the consumption of these foods by children (r = +0.30; p = 0.006) and the lower their subscapular skinfold (SSF) thickness (p = 0.011; β = -0.278). On the other hand, the higher the maternal consumption of ultra-processed foods, the higher the children's tricipital skinfold (TSF) thickness (p = 0.010; β = +0.274) and SSF (p = 0.043; β = +0.222). Maternal diet quality was associated with the diet and body composition of children.


Klotho Regulates Cigarette Smoke-Induced Autophagy: Implication in Pathogenesis of COPD.
Chronic obstructive pulmonary disease is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a fundamental cellular process that eliminates long-lived proteins and damaged organelles through lysosomal degradation pathway, though its role in human diseases remains unclear. We hypothesized that an anti-aging protein, Klotho plays an important role in regulating autophagy in response to cigarette smoke (CS). Autophagy was measured by detecting LC3-I and LC3-II expressions. The regulation of autophagy expression by cigarette smoke extract (CSE) was studied in vitro, and small-interfering RNA (siRNA) and recombinant Klotho were employed to investigate the role of Klotho on CSE-induced autophagy. Protein levels and phosphorylation were measured by Western blot assay. CS exposure resulted in induction of autophagy in alveolar macrophages. Pretreatment of cells with Klotho attenuated CS-induced autophagy whereas knockdown of Klotho augmented CS-induced autophagy. Klotho inhibited phosphorylation of ERK, Akt, and IGF-1 in CSE-stimulated cells. These data suggest that Klotho plays a critical role in the regulation of CS-induced autophagy and have important implications in understanding the mechanisms of CS-induced cell death and senescence.


Probable multigeneric resistance to macrocyclic lactone anthelmintics in cattle in New Zealand.
To establish the efficacy of topical formulations of eprinomectin and abamectin against naturally acquired abomasal and small intestinal nematode infections in cattle purchased from a North Island bull-beef property. A controlled slaughter trial, involving eighteen 6-8-month-old mixed breed calves, was conducted in May 2002.The animals were randomly allocated on the basis of faecal egg count to one of three equal-sized groups (n=6), consisting of an untreated control group and two treatment groups. One of the treatment groups was treated with a topical formulation of eprinomectin, the other with abamectin. Both anthelmintics were administered as a single topical treatment on an individual liveweight basis, at the manufacturer's recommended dose rates of 0.5 mg/kg. All calves were housed in separate groups with no access to pasture throughout the entire trial and were slaughtered 7-10 days after treatment. Both anthelmintic treatments were highly effective(worm count reduction >98%) against Ostertagia ostertagi, Trichostrongylus axei and Cooperia punctata, but were not effective at reducing worm counts significantly of either Cooperia oncophora or Trichostrongylus longispicularis. Against these latter two parasites, worm count reductions of only 72% and 79%, and 81% and 76%, respectively, were recorded following treatment with eprinomectin or abamectin, respectively (all p>0.05). These results demonstrate evidence of resistance to macrocyclic lactone anthelmintics by C. oncophora and probably T. longispicularis also. As well as perhaps providing the first record of resistance to any anthelmintic by T. longispicularis, the present findings may also represent the first case of resistance to macrocyclic lactone anthelmintics exhibited by more than one parasite species at a time in cattle in New Zealand.


A known technique for meniscal repair in common practice.
In this retrospective study, we calculated the healing rate of meniscal repairs performed with an outside-in technique. We describe complications encountered and evaluate some known criteria used in the decision to perform a meniscal repair instead of partial meniscectomy. Included is a brief description of the surgical technique and of the trauma type and the meniscal lesions that were repaired. The technique has a high degree of success (74% of the meniscal repairs survived during a mean follow-up of 3.5 years). Although there is a 25% complication rate, no serious or permanent complications were added by repairing menisci instead of performing a partial meniscectomy. For this reason we think saving even a relatively low percentage of menisci may be worthwhile. We can also conclude that an anterior cruciate ligament-deficient knee that is stable can still have a good result in meniscal repair, without performing cruciate reconstruction. In each case, however, individual patient issues such as age, activity level, and associated lesions have to be considered.


Questioning the role of palmitoylethanolamide in psychosis: a systematic review of clinical and preclinical evidence.
The endocannabinoid (eCB) system disruption has been suggested to underpin the development of psychosis, fueling the search for novel, better-tolerated antipsychotic agents that target the eCB system. Among these, palmitoylethanolamide (PEA), an N-acylethanolamine (AE) with neuroprotective, anti-inflammatory, and analgesic properties, has drawn attention for its antipsychotic potential. This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020-compliant systematic review aimed at reappraising all clinical and preclinical studies investigating the biobehavioral role of PEA in psychosis. Overall, 13 studies were eligible for data extraction (11 human, 2 animal). Observational studies investigating PEA tone in psychosis patients converged on the evidence for increased PEA plasma (6 human) and central nervous system (CNS; 1 human) levels, as a potential early compensatory response to illness and its severity, that seems to be lost in the longer-term (CNS; 1 human), opening to the possibility of exogenously supplementing it to sustain control of the disorder. Consistently, PEA oral supplementation reduced negative psychotic and manic symptoms among psychosis patients, with no serious adverse events (3 human). No PEA changes emerged in either preclinical psychosis model (2 animal) studied. Evidence supports PEA signaling as a potential psychosis biomarker, also indicating a therapeutic role of its supplementation in the disorder. https://doi.org/10.17605/OSF.IO/AFMTK.


Grape aroma precursors in cv. Nebbiolo as affected by vine microclimate.
The influence exerted by bunch microclimate on some C13-norisoprenoid precursors content was investigated for the first time in Nebbiolo grapes during ripening. Samples were collected, during two consecutive seasons, from two vineyards, which are characterized by different microclimatic conditions caused by vine vigour heterogeneity and different vineyard aspects. Enzymatic hydrolysis of the glycosides extracted from the grapes, and subsequent GC-MS determination of the aglycones, highlighted that the majority of norisoprenoid glycosides accumulated in Nebbiolo berries from pre-veraison until 3-4weeks post-veraison. Vineyard aspect and vine vigour affected the timing of the maximum concentration of norisoprenoid precursors and their subsequent decrease at harvest. Low light in the vigorous blocks penalized norisoprenoids peak concentration. In the south less vigorous blocks, a decline of total norisoprenoids content during the pre-harvest period was observed. This decline appeared mainly regulated by the temperature. Vintage and/or microclimatic conditions affected the final content of some important norisoprenoids.


Biphasic finite element contact analysis of the knee joint using an augmented Lagrangian method.
Biphasic contact analysis is essential to obtain a more complete understanding of soft tissue biomechanics; however, only a limited number of studies have addressed these types of problems. In this paper, a theoretically consistent biphasic finite element solution of the 2D axisymmetric human knee was developed, and an augmented Lagrangian method was used to enforce the biphasic continuity across the contact interface. The interaction between the fluid and solid matrices of the soft tissues of the knee joint, the stress and strain distributions within the meniscus, and the changes in stress and strain distributions in the articular cartilage of the femur and tibia after complete meniscectomy were investigated. It was found that (i) the fluid phase carries more than 60% of the load, which reinforces the need for the biphasic model for knee biomechanics; (ii) the inner third and outer two-thirds of the meniscus had different strain distributions; and (iii) the distributions of both maximum shear stress and maximum principal strain in articular cartilage changed after complete meniscectomy - with peak values increasing by over 350%.


Range-of-motion affects cartilage fluid load support: functional implications for prolonged inactivity.
Joint movements sustain cartilage fluid load support (FLS) through a combination of contact migration and periodic bath exposure. Although there have been suggestions that small involuntary movements may disrupt load-induced exudation during prolonged inactivity, theoretical studies have shown otherwise. This work used well-controlled explant measurements to experimentally test an existing hypothesis that the range-of-motion must exceed the contact length to sustain non-zero FLS. Smooth glass spheres (1.2-3.2 mm radius) were slid at 1.5 mm/s (Péclet number >100) against bovine osteochondral explants under varying normal loads (0.05-0.1 N) and migration lengths (0.05-7 mm) using a custom instrument. In situ deformation measurements were used to quantify FLS. Non-zero FLS was maintained at migration lengths as small as 0.05 mm or <10% the typical contact diameter. FLS peaked when track lengths exceeded 10 times the contact diameter. For migration lengths below this threshold, FLS decreased with increased contact stress. Migration lengths far smaller than the contact diameter can sustain non-zero FLS, which, from a clinical perspective, indicates that fidgeting and drifting can mitigate exudation and loss of FLS during prolonged sitting and standing. Nonetheless, FLS decreased monotonically with decreased migration length when migration lengths were less than 10 times the contact diameter. The results demonstrate: (1) potential biomechanical benefits from small movement (e.g., drifting and fidgeting); (2) the quantitative limits of those benefits; (3) and how loads, movement patterns, and mobility likely impact long term FLS.


Chemical defense in birch: Inhibition of digestibility in ruminants by phenolic extracts.
The biological activity of phenolic extracts originating from winter twigs of birch (Betula pendula Roth.) was measured using the ruminant in vitro method and the nylon bag technique. Different extracts were prepared by extraction with organic solvents, removing phenols of corresponding solubility. The extract of birch twigs (diameter <1.5 mm) contained about 19% phenol equivalents, corresponding to 6% of twig dry matter (DM). Coarse birch twigs (diameter 1.5-5 mm) contained about 3% in the DM Phenolic extracts from the fine birch twigs were added to coarse birch twigs and common timothy (Phleum pratense L.) to mimic natural concentrations of fine birch twigs. Controls and the plant material with phenolic extract added were incubated for different times with rumen inocula taken from a sheep fed browse and a goat fed hay. Nylon bags containing phenolic treated hay were incubated in the rumen of the goat for 6 and 48 h. Phenolic extracts had a considerable negative effect on the organic matter (OM), protein and cell wall (neutral detergent fiber, NDF) digestibility in vitro. The nylon bag OM disappearance was also depressed by the extract. The effects were measurable after 6 h of digestion both in vitro and in sacco.The high inhibitory effect by the extracts on digestibility persisted even after removal of lipophilic fractions. This suggests that some or several water-soluble phenolic substances are responsible for the depression of digestibility. The depression of OM digestibility is linearly related to the concentration of phenols added. However, the inhibition of nylon bag digestibility plateaus at high phenol concentrations, suggesting that some fraction of the substances undergo complex formation with macromolecules of the plant.The results strongly indicate that water-soluble phenols of birch make up an important part of its chemical defense in winter by possessing antinutritional properties. Thus their potential importance in the nutrition of wild herbivores must not be ignored.


HIV-infected patients rarely develop invasive fungal diseases under good immune reconstitution after ART regardless high prevalence of pathogenic filamentous fungi carriage in nasopharynx/oropharynx.
We aimed to investigate the prevalence and risk factors of filamentous fungi (FF) carriage in human immunodeficiency virus (HIV)-infected patients in Guangdong province, along with its subsequent incidence of invasive fungal disease (IFD). Seven hundred and sixteen HIV-infected individuals from the outpatient clinic and 293 sex-matched healthy controls were recruited prospectively from May 1 to August 31, 2017. Fungi were isolated from oropharyngeal and nasopharyngeal swabs, then identified by morphological and molecular biological techniques. Logistic regression analysis was used to identify risk factors of pathogenic FF carriage. Pathogenic FF carriers were followed up through the end of 2019. Of the 716 included HIV-infected patients, 602 (84.1%) were male, the median age was 34 (27-42) years, and the median CD4+ count was 385 (254-542) cells/μl. Pathogenic FF were isolated in 119 (16.6%) cases with HIV infection and 40 (13.7%) healthy controls. Mucorales were found in 3 HIV-infected individuals and Talaromyces marneffei in 2 HIV-infected individuals, but not in healthy controls. History of cured opportunistic infections (OIs; OR, 1.97; 95% CI, 1.23-3.13, p = 0.004), and smoking (OR, 1.55; 95%CI, 1.03-2.32, p = 0.035) were independent risk factors of pathogenic FF carriage in HIV-infected individuals. A total of 119 pathogenic FF carriers with HIV infection were followed. During follow-up, 119 (100%) cases received antiretroviral therapy (ART) for at least 28 months, 107 (90%) cases had CD4+ counts>200 cells/μl, and none developed IFD. Pathogenic FF carriage is common in HIV-infected individuals but may not develop IFD in those who achieved immune reconstitution. Smoking and cured OIs history increase the risk of pathogenic FF carriage. Smoking abstinence and ART adherence are especially important for these patients.


A comparison of two anesthetic techniques for the study of rat skeletal muscle high-energy phosphates in vivo using 31P-NMR.
31P-Nuclear magnetic resonance (NMR) spectroscopy was used to evaluate in vivo rat quadriceps ATP, phosphocreatine (PCr), inorganic phosphate (Pi) and tissue pH during anesthesia with ketamine/xylazine (K/X) or isoflurane (IS). A surface coil was used to receive signals from the quadriceps muscle of rats positioned in a wide-bore horizontal magnet. The PCr/beta-ATP ratios determined from the NMR spectra were 4.34 +/- 0.19 (K/X) and 4.40 +/- 0.28 (IS). Tissue pH was 7.09 +/- 0.05 (K/X) and 7.13 +/- 0.07 (IS). Metabolic stability of quadriceps PCr and ATP was demonstrated during both K/X and IS anesthesia, but the K/X-anesthetized animals had longer sleep time, lower food consumption, and lower body weight post-anesthesia than the IS-anesthetized animals. The PCr/beta-ATP ratio in quadriceps of repetitively IS-anesthetized rats did not fluctuate diurnally. In addition, the animals recovered rapidly and continued to gain weight following the multiple brief IS anesthetic procedures. These data indicate that serial in vivo investigations of high-energy-phosphate metabolism in small animals can be accomplished using 31P-NMR spectroscopy and IS anesthesia, which has several advantages over K/X anesthesia for these types of studies.


[Camptodactylies].
Camptodactyly is a permanent non-traumatic flexion contracture at the proximal interphalangeal joint, involving most of the time the fifth finger. This condition is rare (incidence is inferior to 1%). Most of the cases are sporadic, although some authors have traced the transmission through several generations. Two types of camptodactyly have been described, depending on the age of onset (within the first year of age or in adolescent). This condition can also be described as "static" or "dynamic", depending on the effect of MP flexion on the PIP extension lag. Many anatomical abnormalities have been evoked as potential aetiology for camptodactyly, including variations in the lumbrical or flexor superficialis origin or distal insertions. However, after a few years without treatment, permanent flexion position of the joint adds its own effects and leads to joint contracture, regardless of the aetiology of camptodactyly. Treatment is required for this condition for extension deficit greater than 30 degrees. The first step will always consists of dynamic splinting of the PIP joint. If improvement is not obtained through dynamic splinting alone, surgery can be considered. Correction of a well defined anatomical abnormality is part of the treatment. When required, it will be associated to correction of joint and soft tissue contracture.


Ultrasound and nerve stimulator guidance lumbar transforaminal epidural block for the treatment of patients with lumbosacral radicular pain.
Transforaminal epidural block (TEB) is a widely accepted technique and minimally invasive procedure for the treatment of lumbosacral radicular pain. This study aimed to evaluate the accuracy, efficacy, and safety of ultrasound and nerve stimulator guidance lumbar transforaminal epidural block (UNTEB) for the patients with unilateral lower lumbar radicular pain. The accuracy of this method was evaluated by fluoroscopy. Using UNTEB via axial and the in-plane approach technique was performed in 42 segments of 25 patients who presented with lumbosacral radicular pain to lower extremities. The contrast medium was injected to evaluate the needle tip at the intervertebral foramen under fluoroscopic guidance. The numerical rating scale was used to assess pain before and after treatment. The success ratio of UNTEB in L3/L4 level was 100%, in L4/L5 was 95.4% and in L5/S1 was 100%. The numerical rating scale (NRS) for lumbosacral radicular pain improved from a mean from 7.8 to 2.8 1 day after procedure (p = 0.01) and from a mean from 7.8 to 2.4 1 week after UNTEB (p = 0.01). None of our subjects experienced any complications during and after the procedure. UNTEB with fluoroscopic validation is an accurate, effective, and safe method for short-term pain relief of the patients with unilateral lumbosacral radicular pain.


Early postnatal development of vasoactive intestinal polypeptide- and peptide histidine isoleucine-immunoreactive structures in the cat visual cortex.
The early postnatal development of neurons containing vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI) has been analyzed in visual areas 17 and 18 of cats aged from postnatal day (P) 0 to adulthood. Neuronal types are established mainly by axonal criteria. Both peptides occur in the same neuronal types and display the same postnatal chronology of appearance. Several cell types are transient, which means that they are present in the cortex only for a limited period of development. According to their chronology of appearance the VIP/PHI-immunoreactive (ir) cell types are grouped into three neuronal populations. The first population comprises six cell types which appear early in postnatal life. The pseudohorsetail cells of layer I possess a vertically descending axon which initially gives rise to recurrent collaterals, then forms a bundle passing layers III to V, and finally, horizontal terminal fibers in layer VI. The neurons differentiate at P 4 and disappear by degeneration around P 30. The neurons with columnar dendritic fields of layers IV/V are characterized by a vertical arrangement of long dendrites ascending or descending parallel to each other, thus forming an up to 600 microns long dendritic column. Their axons always descend and terminate in broad fields in layer VI. The neurons appear at P 7 and are present until P 20. The multipolar neurons of layer VI occur in isolated positions and have broad axonal territories. The neurons differentiate at P 7 and persist into adulthood. Bitufted to multipolar neurons of layers II/III have axons descending as a single fiber to layer VI, where they terminate. The neurons appear at P 12 and persist into adulthood. The four cell types described above issue a vertically oriented fiber architecture in layers II-V and a horizontal terminal plexus in layer VI which is dense during the second, third and fourth week. Concurrent with the disappearance of the two transient types the number of descending axonal bundles and the density of the layer VI plexus is reduced, but the latter is maintained during adulthood by the two persisting cell types. Two further cell types belong to the first population: The transient bipolar cells of layers IV, V, and VI have long dendrites which extend through the entire cortical width. Their axons always descend, leave the gray matter, and apparently terminate in the upper white matter. The neurons differentiate concurrently with the pseudohorsetail cells at P 4, are very frequent during the following weeks, and eventually disappear at P 30.(ABSTRACT TRUNCATED AT 400 WORDS)


Oxidation of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) by Alcaligenes eutrophus A5.
Previous studies demonstrated that Alcaligenes eutrophus A5 transforms 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) to 4-chlorobenzoate via a meta-ring fission product. The initial reactions could be catalyzed by either monooxygenase or dioxygenase enzymes. In the present study, a transient intermediate that accumulated during the transformation of DDT by the biphenyl-grown cells was identified as 1,1,1-trichloro-2-(4-chlorophenyl-2,3-dihydro-4,6-cyclohexadiene)-2-(4'- chlorophenyl)ethane (DDT-2,3-dihydrodiol) on the basis of mass spectral analysis after n-butylboronic acid derivatization. The dihydrodiol undergoes a characteristic acid-catalyzed dehydration to produce phenols. 1H-NMR indicated a cis-relative stereochemistry. The results indicate that the biphenyl dioxygenase from A. eutrophus A5 catalyzes the dihydroxylation of DDT at the unsubstituted carbons on the aromatic ring to produce DDT-2,3-dihydrodiol.


Synthesis of silicon and germanium containing heteroaromatic sulfides as cholesterol level lowering and vasodilating agents.
Silicon and germanium containing heteroaromatic sulfides have been prepared using phase transfer catalytic (PTC) system thiol / Si or Ge containing alkyl halide / solid KOH / 18- crown-6 / toluene. The target sulfides were isolated in yields up to 92 %. It has been found that 2-{[dimethyl (beta-triethylgermylethyl)-silylmethyl]thio}-1-methylimidazole and 2-{[dimethyl(beta-triphenylsilylethyl) silyl-methyl]thio}benzothiazole are the most active cholesterol level lowering and vasodilating agents.


Description and evaluation of adaptations to the global trigger tool to enhance value to adverse event reduction efforts.
To adapt the Global Trigger Tool (GTT) as a sustainable monitoring tool able to characterize adverse events (AEs) for organizational learning, within the context of limited resources. Baylor Health Care System (BHCS) expanded the AE data collected to include judgments of preventability, presence on admission, relation to care provided or not provided, and narrative descriptions. To reduce costs, we focused on patients with length of stay (LOS) of 3 days or more, suspecting greater likelihood they had experienced an AE; adapted the sample size and frequency of review; and used a single nurse reviewer followed by quality assurance review within the Office of Patient Safety. We compared AE rates in patients with LOS of less than 3 days versus 3 days or greater, assessed trigger yields and interrater reliability, and submitted identified AEs to each hospital for validation as event types targeted for reduction. In 2008, 91% of identified AEs were in patients with LOS of 3 days or greater; there were 6.4 AEs per 100 discharges with LOS of less than 3 days versus 27.1 AEs per 100 discharges with LOS of 3 days or greater. Over 4 years, we reviewed 16,172 medical records; 14,184 had positive triggers, 17.1% of which were associated with an AE. Most AEs were identified via the "surgical" (36.3%) and "patient care" (36.0%) trigger modules. Reviewers showed fair to good agreement (κ = 0.62), and hospital clinical leaders strongly agreed that the identified events were AEs. The GTT can be adapted to health-care organizations' goals and resource limitations. This flexibility was essential in crossing our organization's "value threshold."


Military humanitarian and disaster governance networks in Southeast Asia: framework and analysis.
Behind humanitarian assistance and disaster relief (HADR) efforts are governance networks of actors working together to facilitate, coordinate, and deliver joint aid and response initiatives. Militaries are key stakeholders in these networks because of their unique capabilities, particularly in Southeast Asia. This paper explores the role of military governance networks in shaping HADR affairs. It presents a framework for examining military-to-military relational structures in humanitarian and disaster contexts using network theory and social network analysis. It also assesses the nature of military ties and their influence on two capability areas essential to humanitarian activities in the region: (i) the distribution of military assets and equipment used in HADR; and (ii) the coordination of HADR exercises and training. This paper seeks to provide insights into how governance network features and properties affect the capacity of ASEAN (Association of Southeast Asian Nations) militaries to use available resources efficiently and to achieve shared objectives in regional disaster response.


Subclinical hypothyroidism and the risk of metabolic syndrome: A meta-analysis of observational studies.
Observational studies on the association between subclinical hypothyroidism (SCH) and metabolic syndrome (MetS) have produced inconsistent results. Therefore, we performed a meta-analysis to evaluate the effect of SCH on the risk of MetS. Multiple databases were searched to identify studies on the association between SCH and the risk of MetS, up to February 2015. Relevant information for analysis was extracted. A random-effects model was used to calculate the pooled risk estimates. 9 studies (7 cross-sectional and 2 case-control studies) were included. The pooled odds ratio (OR) for MetS comparing SCH with euthyroid subjects was 1.31 (95%CI: 1.08 to 1.60, p = 0.006, I(2) = 50%). Subgroup analyses by countries revealed a significant association for the studies from Asian (OR = 1.244, 95% CI: 1.030-1.503, I(2) = 25%) other than non-Asian (OR = 1.548, 95% CI: 0.925-2.591, I(2) = 73.5%) countries. A positive association was identified in the IDF subgroup (OR = 1.288, 95% CI: 1.055-1.572, I(2) = 0%), but not in the NCEP-ATP III (OR = 1.351, 95% CI: 0.950-1.923, I(2) = 66.4%), Chinese (OR = 1.430, 95% CI: 0.891-2.294) and Japanese (OR = 1.542, 95% CI: 0.594-4.005, I(2) = 78.3%) subgroup. A certain degree of heterogeneity was observed among studies which cannot be explained by study design, diagnostic criteria and location. Our results demonstrated that SCH was significantly associated with a higher risk of MetS. Well-designed cohort studies were warranted to confirm our findings.


Immature mice are more susceptible to the detrimental effects of high fat diet on cancellous bone in the distal femur.
With the increasing prevalence of obesity among children and adolescents, it is imperative to understand the implications of early diet-induced obesity on bone health. We hypothesized that cancellous bone of skeletally immature mice is more susceptible to the detrimental effects of a high fat diet (HFD) than mature mice, and that removing excess dietary fat will reverse these adverse effects. Skeletally immature (5weeks old) and mature (20weeks old) male C57BL/6J mice were fed either a HFD (60% kcal fat) or low fat diet (LFD; 10% kcal fat) for 12weeks, at which point, the trabecular bone structure in the distal femoral metaphysis and third lumbar vertebrae were evaluated by micro-computed tomography. The compressive strength of the vertebrae was also measured. In general, the HFD led to deteriorations in cancellous bone structure and compressive biomechanical properties in both age groups. The HFD-fed immature mice had a greater decrease in trabecular bone volume fraction (BVF) in the femoral metaphysis, compared to mature mice (p=0.017 by 2-way ANOVA). In the vertebrae, however, the HFD led to similar reductions in BVF and compressive strength in the two age groups. When mice on the HFD were switched to a LFD (HFD:LFD) for an additional 12weeks, the femoral metaphyseal BVF in immature mice showed no improvements, whereas the mature mice recovered their femoral metaphyseal BVF to that of age-matched lean controls. The vertebral BVF and compressive strength of HFD:LFD mouse bones, following diet correction, were equivalent to those of LFD:LFD mice in both age groups. These data suggest that femoral cancellous metaphyseal bone is more susceptible to the detrimental effects of HFD before skeletal maturity and is less able to recover after correcting the diet. Negative effects of HFD on vertebrae are less severe and can renormalize with LFD:LFD mice after diet correction, in both skeletally immature and mature animals.


LPA suppresses T cell function by altering the cytoskeleton and disrupting immune synapse formation.
Cancer and chronic infections often increase levels of the bioactive lipid, lysophosphatidic acid (LPA), that we have demonstrated acts as an inhibitory ligand upon binding LPAR5 on CD8 T cells, suppressing cytotoxic activity and tumor control. This study, using human and mouse primary T lymphocytes, reveals how LPA disrupts antigen-specific CD8 T cell:target cell immune synapse (IS) formation and T cell function via competing for cytoskeletal regulation. Specifically, we find upon antigen-specific T cell:target cell formation, IP3R1 localizes to the IS by a process dependent on mDia1 and actin and microtubule polymerization. LPA not only inhibited IP3R1 from reaching the IS but also altered T cell receptor (TCR)–induced localization of RhoA and mDia1 impairing F-actin accumulation and altering the tubulin code. Consequently, LPA impeded calcium store release and IS-directed cytokine secretion. Thus, targeting LPA signaling in chronic inflammatory conditions may rescue T cell function and promote antiviral and antitumor immunity.


Interventions in management of dental fluorosis, an endemic disease: A systematic review.
Mottling and pitting of enamel due to excess fluoride consumption may affect one's self-esteem due to unaesthetic appearance and also in turn can affect the quality of life. This present study was conducted to assess various treatment approaches available for patients with dental fluorosis. Literatures were searched from August 1998 to August 2019 for articles in the management of dental fluorosis. The databases used were National Center for Biotechnology Information (NCBI) and Google Scholar. In NCBI, the filters were modified to randomized controlled trial, clinical trial, human trial, and free full-text articles. The following queries were used in order to search for the article: treatment for dental fluorosis, intervention of dental fluorosis, and management of dental fluorosis. All the five studies selected after screening were randomized controlled trials. Total number of patients included in this study were 304 with the mean age of 17.7 years old. They were treated with microabrasion, bleaching, resin infiltration or combination of microabrasion with bleaching, and resin infiltration with bleaching. Microabrasion resulted in less esthetic improvement compared with bleaching. Meanwhile, resin infiltration showed a greater improvement in esthetics in comparison to bleaching. Resin infiltration with additional infiltration time and combination of resin infiltration with bleaching are the best treatment options. Based on this systematic review, resin infiltration with increased infiltration time is the best treatment approach in treating dental fluorosis.


Stalking influenza by vaccination with pre-fusion headless HA mini-stem.
Inaccuracies in prediction of circulating viral strain genotypes and the possibility of novel reassortants causing a pandemic outbreak necessitate the development of an anti-influenza vaccine with increased breadth of protection and potential for rapid production and deployment. The hemagglutinin (HA) stem is a promising target for universal influenza vaccine as stem-specific antibodies have the potential to be broadly cross-reactive towards different HA subtypes. Here, we report the design of a bacterially expressed polypeptide that mimics a H5 HA stem by protein minimization to focus the antibody response towards the HA stem. The HA mini-stem folds as a trimer mimicking the HA prefusion conformation. It is resistant to thermal/chemical stress, and it binds to conformation-specific, HA stem-directed broadly neutralizing antibodies with high affinity. Mice vaccinated with the group 1 HA mini-stems are protected from morbidity and mortality against lethal challenge by both group 1 (H5 and H1) and group 2 (H3) influenza viruses, the first report of cross-group protection. Passive transfer of immune serum demonstrates the protection is mediated by stem-specific antibodies. Furthermore, antibodies induced by these HA stems have broad HA reactivity, yet they do not have antibody-dependent enhancement activity.


Mutations in LPAR6/P2RY5 and LIPH are associated with woolly hair and/or hypotrichosis.
Woolly hair (WH) belongs to a family of disorders characterized by hair shaft anomalies that clinically presents with tightly curled hair, which can be divided into syndromic and non-syndromic forms of WH. We have recently identified mutations in both LPAR6/P2RY5 and LIPH that are associated with autosomal recessive woolly hair (ARWH). To study the underlying genetic causes of autosomal woolly hair in Pakistani population. We studied 10 Pakistani families with ARWH for mutations in LPAR6/P2RY5 and LIPH and then performed haplotype analysis to confirm their segregation in the families. We identified five mutations in LPAR6/P2RY5, among which three were recurrent and two were novel in eight Pakistani families. We then showed that two of the mutations in LPAR6/P2RY5 are founder mutations in Pakistani families. Moreover, we identified two recurrent mutations in the LIPH gene in two Pakistani families. Our study extends the spectrum of mutations in LPAR6/P2RY5 gene and underscores those mutations in LPAR6/P2RY5 and LIPH result in similar phenotypes.


Copy Number Alterations as Novel Biomarkers and Therapeutic Targets in Colorectal Cancer.
In colorectal cancer, somatic mutations have played an important role as prognostic and predictive biomarkers, with some also functioning as therapeutic targets. Another genetic aberration that has shown significance in colorectal cancer is copy number alterations (CNAs). CNAs occur when a change to the DNA structure propagates gain/amplification or loss/deletion in sections of DNA, which can often lead to changes in protein expression. Multiple techniques have been developed to detect CNAs, including comparative genomic hybridization with microarray, low pass whole genome sequencing, and digital droplet PCR. In this review, we summarize key findings in the literature regarding the role of CNAs in the pathogenesis of colorectal cancer, from adenoma to carcinoma to distant metastasis, and discuss the roles of CNAs as prognostic and predictive biomarkers in colorectal cancer.


Geographic variations in life-history traits of the intertidal ocypodid crab Macrophthalmus banzai.
Reproductive traits of the mud crab Macrophthalmus banzai were compared in populations from Okinawa (26°13' N) and Amakusa (32°32' N). Crabs matured earlier and at a smaller size in Okinawa than in Amakusa, but growth rate did not differ between the two localities. Population density was much higher in Okinawa. Breeding occurred in winter in Okinawa and in summer in Amakusa. In Okinawa, females produced one brood at over 1 year of age and then died. In Amakusa, females produced one brood at over 1 year of age, and one or two broods at around 2 years of age, and then died. Egg weight in the Okinawa population was almost twice that of the Amakusa population. Furthermore, brood weight was larger in Okinawa than in Amakusa. Longevity was 16-19 months in Okinawa and 28-30 months in Amakusa. At high latitudes, the winter low temperature blocks reproduction of M. banzai. At low temperature blocks reproduction of M. banzai. At low latitudes, their short lifespan prevents iterative breeding. Thus, the difference in breeding season greatly affects other life-history traits.


Histocompatibility antigens in patients with hepatocellular carcinoma and their relationship to chronic hepatitis B virus infection in these patients.
Although hepatocellular carcinoma is probably caused by one or more environmental carcinogens, a genetically determined susceptibility to the development of the tumor has not been excluded. In looking for such a predisposition, we have compared the histocompatibility antigens (HLA) of 102 southern African blacks with histologically proved HCC with those of 208 healthy blacks. The standard two-stage lymphocyte microcytotoxicity method was used to test for 40 antigens: 17 in the A locus, 20 in the B locus, and 3 in the C locus. None of the HLA antigens had a frequency that was significantly different in the patients and the controls. A close association undoubtedly exists between chronic hepatitis B virus infection and hepatocellular carcinoma. If this virus is proved to be oncogenic with respect to hepatocellular carcinoma, a genetic predisposition to the hepatitis B virus carrier state may have an indirect bearing on the etiology of the tumor. Sera from the hepatocellular carcinoma patients were therefore tested for hepatitis B virus markers (HBV surface antigen and antibody against HBV core antigen), and these were related to the patients' histocompatibility antigens. None of the HLA antigen frequencies was significantly different in the surface antigen-positive and the surface antigen-negative patients. As 88% of the patients were anticore positive, no meaningful correlation could be carried out with this marker. Analysis of histocompatibility antigens thus failed to show evidence of a genetic predisposition either to hepatocellular carcinoma or to chronic hepatitis B surface antigenemia in patients with this tumor.


IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.
The recent discovery of CD4(+) T cells characterized by secretion of interleukin (IL)-17 (T(H)17 cells) and the naturally occurring regulatory FOXP3(+) CD4 T cell (nT(reg)) has had a major impact on our understanding of immune processes not readily explained by the T(H)1/T(H)2 paradigm. T(H)17 and nT(reg) cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. Our recent data and the work of others demonstrated that transforming growth factor-beta (TGF-beta) and IL-6 are responsible for the differentiation of naive mouse T cells into T(H)17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T(H)17 phenotype. A second pathway has been discovered in which a combination of TGF-beta and IL-21 is capable of inducing differentiation of mouse T(H)17 cells in the absence of IL-6 (refs 6-8). However, TGF-beta and IL-6 are not capable of differentiating human T(H)17 cells and it has been suggested that TGF-beta may in fact suppress the generation of human T(H)17 cells. Instead, it has been recently shown that the cytokines IL-1beta, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4(+) T cell lines isolated from human peripheral blood, although the factors required for differentiation of naive human CD4 to T(H)17 cells are still unknown. Here we confirm that whereas IL-1beta and IL-6 induce IL-17A secretion from human central memory CD4(+) T cells, TGF-beta and IL-21 uniquely promote the differentiation of human naive CD4(+) T cells into T(H)17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T(H)17 cells in human inflammatory disease.


Identification of new human cadherin genes using a combination of protein motif search and gene finding methods.
We have combined protein motif search and gene finding methods to identify genes encoding proteins containing specific domains. Particularly, we have focused on finding new human genes of the cadherin superfamily proteins, which represent a major group of cell-cell adhesion receptors contributing to embryonic neuronal morphogenesis. Models for three cadherin protein motifs were generated from over 100 already annotated cadherin domains and used to search the complete translated human genome. The genomic sequence regions containing motif "hits" were analyzed by eukaryotic GeneMark.hmm to identify the exon-intron structure of new genes. Three new genes CDH-J, PCDH-J and FAT-J were found. The predicted proteins PCDH-J and FAT-J were classified into protocadherin and FAT-like subfamilies, respectively, based on the number and organization of cadherin domains and presence of subfamily-specific conserved amino acid residues. Expression of FAT-J was shown in almost all tested tissues. The exon-intron organization of CDH-J was experimentally verified by PCR with specifically designed primers and its tissue-specific expression was demonstrated. The described methodology can be applied to discover new genes encoding proteins from families with well-characterized structural and functional domains.


Evidence for coordination of lysosomal (ASMase) and plasma membrane (NSMase2) forms of sphingomyelinase from mutant mice.
NSMase2 is associated to the plasma membrane, whereas ASMase is predominantly lysosomal; both hydrolyze sphingomyelin (SM) to ceramide and phosphocholine. Although SM accumulated in both ASMase(-/-) and fro/fro (NSMase2(-/-)) fibroblasts, the reduction of ceramides was more dramatic in fro/fro cells. ASMase mRNA, protein and enzyme activity were substantially elevated in fro/fro fibroblasts. In contrast, NSMase2 activity was unaffected in ASMase(-/-) fibroblasts. ASMase(-/-) cells showed normal cell cycling whereas fro/fro cells grew slowly and were arrested in G1/G0 and could be corrected by transfection with smpd3 gene. This suggests two distinct subcellular pathways for SM catabolism with distinct functions.


Interatrial Septal Mass Secondary to Rosai-Dorfman Disease: A Rare Cause of Complete Heart Block.
Varying degrees of atrioventricular block can be associated with old age or a manifestation of an ischemic, metabolic, or infective pathology. In patients with no clear explanation, it is important to investigate secondary causes. Our case describes the first case of an adult with Rosai-Dorfman histiocytosis presenting with complete heart block. (Level of Difficulty: Advanced.).


Urological accessory splenic tissue.
We report a case of an asymptomatic pelvic mass that was found during examination for a left ureteral stone. After stone management preoperative computerized tomography demonstrated a 6 by 6 cm. midline pelvic mass posterior to the bladder. Lumbar angiography was normal. A liver/spleen scan and splenic angiography were not performed. At exploration the mass was found to be an accessory pelvic spleen. The embryology, presentation, diagnosis and treatment are discussed.


Specific monoclonal antibodies and human immunoglobulin E show that Hev b 5 is an abundant allergen in high protein powdered latex gloves.
Hev b 5 is a major latex allergen recognized predominantly by latex-allergic health care workers (HCWs). Recombinant Hev b 5 (rHev b 5) was previously expressed as a fusion protein with maltose binding protein (MBP), itself an immunogenic molecule; therefore non-fusion rHev b 5 is desirable. Moreover, standardized immunological assays for the detection of Hev b 5 are currently lacking and may have important implications for both allergen avoidance and diagnosis in latex allergy. To generate and use Hev b 5-specific mAbs to determine the relative abundance of Hev b 5 in different latex extracts, correlating this with the IgE reactivity of latex-allergic HCWs and to produce non-fusion rHev b 5. For the production of mAbs, mice were immunized with rHev b 5/MBP fusion protein and mAbs selected with rHev b 5/MBP but not MBP reactivity. The mAb reactivity was compared with polyclonal IgE from latex-allergic HCWs using direct and inhibition ELISA and immunoblot assays. Recombinant Hev b 5 was expressed and purified in the pPROEX-HTa bacterial expression system. Four Hev b 5-specific mAbs were produced. Immunoblotting and ELISA using the mAbs indicate abundant Hev b 5 in high protein powdered latex glove extracts as compared with crude latex sap extracts. High quality surgical gloves with no detectable protein have no detectable Hev b 5. Inhibition ELISAs using serum IgE from latex-allergic HCWs and Hev b 5-specific mAbs gave strong correlation. Non-fusion recombinant Hev b 5 was successfully expressed and purified, showing reactivity with both the Hev b 5-specific mAbs and serum IgE of latex-allergic HCWs. Hev b 5-specific mAbs and human IgE from latex-allergic HCWs demonstrate the greater content of Hev b 5 in high protein powdered glove extracts. This may explain the observed higher frequency of sensitization to this allergen in HCWs.