An analysis of heterotopic ossification in cervical disc arthroplasty: a novel morphologic classification of an ossified mass.
Although the precise cause of heterotopic ossification (HO) remains unclear, it is certain that it increases with time. The reason why the reported occurrence rate has been given as a wider range is that there were no clinical reports that have addressed the occurrence rate based on the morphology and position. The aim of this retrospective study was to determine whether radiological parameters had an influence on the formation of HO and to compare the results after cervical arthroplasty using Bryan (Medtronic Sofamor Danek, Memphis, TN, USA), PCM (Cervitech, Rockaway, NJ, USA), and Prestige LP (Medtronic Sofamor Danek) implants. A retrospective study. Eighty-one patients were included. The occurrence of HO was determined at the four corners of the disc space according to the McAfee classification system. Heterotopic ossifications were classified into Type 1, Type 2, and Type 3 HOs (end plate, traction spur, and teardrop types) based on their morphologic features. The presence of preoperative ossifications, sex, type of device, operated level, hybrid implantation, depth behind the prosthesis, cervical lordotic angle, and segmental angle between the footplates of the prosthesis were assessed as predictors in terms of location and morphologic features. Eighty-one patients after 95 cervical arthroplasties using the Bryan (35 segments), PCM (30 segments), and Prestige LP implants (30 segments) underwent postoperative radiographs or three-dimensional computed tomography with a mean follow-up period of 46, 39, and 30 months, respectively, after the operation. The overall incidence of all cases and one-level subgroup were 64.2% and 60.3%, respectively. According to the types of device, the incidence of HO was 49% (Bryan), 80% (PCM), and 60% (Prestige). Type 1 HO (62.1%) was found only in the posterosuperior disc space. Type 2 HO (13.7%) was primarily detected in the anterosuperior disc space rather than the posterosuperior disc space (3.2%). Type 3 HO (4.2%) developed only in the anterior disc space. In the anterior disc space, the incidence of Type 2 and Type 3 HOs was highest in the PCM group. In the posterior disc space, the Bryan group showed a lower proportion in the high McAfee class than the other device groups. The occurrence of Type 1 HO in the posterosuperior disc space was significantly related with the presence of preoperative ossification (p=.030), ossification in the ligamentum nuchae (p=.027), male sex (p=.042), and PCM device (p=.012). A well-fitting (p<.002) and less lordotic segmental angle (p<.015) were correlated with Type 1 HO. Implantation in the upper cervical level (p=.016) and hybrid implantation with cage (p=.033) or artificial disc (p=.048) on the upper adjacent level were significant risk factors for anterior Type 2 HO. Cervical lordotic angle at 1 month after surgery had a significant connection with the occurrence of anterior Type 2 HO in both groups of all cases (p=.032) and one-level subgroup (p=.000). Type 1 HO developed mostly in the posterior disc space. Type 2 HO was the dominant type in the anterior disc space. Type 3 HO developed only in the anterior disc space. It is certain that both Type 1 and Type 2 HOs are related to biomechanical stresses (compressive force for Type 1 HO and traction force for Type 2 HO). It is suggested that a cervical arthroplasty should be selected in terms of the implant level, hybrid conditions on the upper adjacent segment, disc design vulnerable to the pseudotranslation, the presence of preoperative ossification, and fitting implants to end plates to reduce the development of HO.


Colonoscopy. First experience in Nigeria.
Colonoscopy is the only major advancement in the diagnosis of colonic diseases since the first barium-enema examination was performed in 1905. The indications are many and contraindications few. If colonoscopy is performed with care, it is safe and the results are rewarding. Patient comfort, integrity, and dignity are essential for the success of the procedure. Five hundred sixty-two colonoscopies were performed during a four-year period in Ife, Nigeria (1978 to 1982). The indications for colonoscopy are discussed and the results presented.


Successful management of a large bronchopleural fistula after lobectomy: report of a case.
The development of bronchopleural fistula after pulmonary resection is a well-known complication associated with a high mortality rate. We herein describe the successful management of a bronchopleural fistula using a rib and intercostal muscle in a patient with a large stump opening of 25 mm in diameter. A flap with rib and intercostal muscle is useful for large bronchopleural fistulas to avoid airway stenosis.


Route exposure and adverse effects monitoring of Aflatoxin B1 in the workers of wet waste management, the role of body redox system modulation.
Exposure to dust, containing different fungi metabolites such as aflatoxins is a risk factor for developing liver and kidney health abnormalities. Occupational evaluation of the aflatoxin's exposure-induced health abnormalities should include the monitoring of bioaerosols in the workplace and personal air, and applying of appropriate blood biomarkers to assess Aflatoxin B1 (AFB1) detrimental effects on a worker's health. However, to the best of our knowledge, these appropriate methods, especially determining the associated-adverse effects on health, following exposure, haven't been well documented in the literature at the wet waste handling sites. In the current study, the AFB1 quantity in the area, personal, and settled dust in wet household waste handling samples and AFB1-Albumin levels in the serum of workers in comparison with the control group were determined using high-pressure liquid chromatography with a fluorescent detector (HPLC-FLD) methods. Moreover, the adverse effects of AFB1 on the liver and kidney biochemical profiles of the exposed workers and its relation to antioxidant capacity in the household wet waste sorting were recorded in a consolidated investigation. The results demonstrated that the average airborne dust concentration and its associated AFB1 content were significantly higher in wet waste management sections as compared to the control place, corresponding to the serum AFB1-Albumin levels of workers. Furthermore, AFB1-induced changes in the serum biochemicals evaluating liver and kidney function tests and antioxidant profiles of workers in wet waste handling sections were indicative of their function abnormalities. The results imply AFB1-induced adverse effects on the liver and kidney functions may be mediated through the body redox system modulation.


Ability of calf brain synaptic membranes to bind [35S]taurine to their triton X-100 and chloroform extracts.
A protein fraction containing reducing sugars was prepared from calf brain synaptic membranes with 0.5% Triton X-100, and another fraction containing bound phosphorus with a 2 : 1 chloroform--methanol mixture. Both protein fractions bound small amounts of [35S]taurine, the first fraction about 25 pmol/g protein and the second about 220 pmol/g protein. The Triton X-100 extract represented 13.8% of the membrane proteins, but the chloroform--methanol extract only 0.9%. The binding of taurine to the Trition X-100 extract was temperature sensitive, but was only slightly inhibited by hypotaurine and beta-alanine.


Examples of electrostatic electron optics: the Farrand and Elektros microscopes and electron mirrors.
The role of Gertrude Rempfer in the design of the Farrand and Elektros microscopes is evoked. The study of electron mirror optics, aberration correction using mirrors and the development of microscopes employing electron mirrors are recapitulated, accompanied by a full bibliography, of earlier publications in particular.


Sweat rates and fluid turnover in professional football players: a comparison of National Football League linemen and backs.
Many National Football League (NFL) teams practice 2 times per day over consecutive days in a hot and humid environment. Large body surface area (BSA) and use of protective equipment result in high sweat rates and total sweat loss in these football players. To compare sweat rate, sweat loss, fluid consumption, and weight loss between NFL linemen and backs during preseason practices. Between-groups design. Preseason training camp with wet bulb globe temperature between 19 degrees C and 25 degrees C. Eight linemen and 4 backs and receivers participated. Data were collected during both practice sessions on 2 separate days during the first week of August. Sweat rate was calculated as change in mass adjusted for all fluids consumed between prepractice and postpractice body mass measurements and the urine produced during practice divided by the length of the practice session. Gross daily sweat losses also were calculated. Height, mass, and BSA were higher in linemen than in backs. Sweat rate was also higher in linemen (2385 +/- 520 mL/h) than in backs (1410 +/- 660 mL/h, P < .001), as was the total volume of sweat lost during both practices in 1 day (6870 +/- 1034 mL/d versus 4110 +/- 2287 mL/d, P = .014). Compared with backs, linemen consumed more fluids during practice (2030 +/- 849 mL versus 1179 +/- 753 mL, P = .025) but produced less urine (53 +/- 73 mL versus 163 +/- 141 mL, P = .018). There was no difference in postpractice weight loss (linemen = -1.15 +/- 0.83%, backs = -1.06 +/- 0.76%). Linemen sweated at higher rates, lost larger volumes of sweat, consumed more fluids, and produced less urine during practice compared with the physically smaller backs, but they did not lose a greater percentage of body weight. Sodium losses could be considerable in NFL players during the preseason because of high daily sweat losses in backs and in linemen.


A study of abnormal cervical cytology in pregnant women.
During the 4-year routing study of smears in 2,919 pregnant women, 33 cases of abnormalities of the uterine cervix were detected (1.13%). The patients were followed with uterine cervical cytology and colposcopy, and in case of need, sometimes punch biopsies were performed. As a result of the cytologies, 33 cases with abnormalities were detected. There were 26 cases classified as class IIIa and 7 cases were class IIIb. All cases underwent colposcopy. For the 17 cases that showed lesions by colposcopy, punch biopsies were performed. The results of histologic examination were wide: 5 chronic cervicitis, 1 condyloma, 1 mild dysplasia, 3 moderate dysplasia, 3 severe dysplasia, 3 carcinoma in situ, and 1 microinvasive carcinoma. Only two cases were treated during pregnancy, condyloma underwent Laser vaporization and microinvasive carcinoma underwent Loop electrosurgical excision procedure (LEEP) conization. Other cases were conservative treatment during pregnancy. Excluding one case for persistence smear class IIIa of histology condyloma, all the other cases with regression of dysplasia and carcinoma in situ with treatment after delivery. We conclude that lesions up to carcinoma in situ do not require intervention during pregnancy but microinvasive carcinoma is suspected, diagnostic LEEP conization is necessary, even during pregnancy.


Ultrasound examination of the hand and foot.
The use of ultrasound in the examination of the distal extremities is a recent application of sonography of the musculotendinous system. Real-time sonography is unique in providing a dynamic study of complex anatomic structures such as the flexor tendons of the hand. The normal anatomic appearance of the hand and foot are reviewed as well as the sonographic appearance of pathologic conditions of the distal extremities.


Quantitative proteomics study of the neuroprotective effects of B12 on hydrogen peroxide-induced apoptosis in SH-SY5Y cells.
B12 belongs to the coumarin class of compounds that have been shown to have various physiological and pharmacological activities including anti-inflammatory, antibacterial, and antioxidant. In the present study, we characterised the neuroprotective effects of B12 against H2O2-induced neuronal cell damage in SH-SY5Y cells. Protein expression profiling in combination with pathway analysis was deployed to investigate the molecular events associated with the neuroprotective effects in human neuronal cells using a label-free quantitative proteomics approach. A total of 22 proteins were significantly differentially expressed in H2O2-damaged cells with or without B12 treatment. Bioinformatics analysis using the Cytoscape platform indicated that poly pyrimidine tract binding protein 1 (PTBP1) was highly associated with the protective effect, and western blotting verified that PTBP1 was up-regulated in H2O2 + B12 treatment group, compared with the H2O2 treated group. PTBP RNAi experiments knocked down PTBP expression, which cancelled out the protective effect of B12 on cell viability. Thus, we infer that B12 neuroprotective activity involves up-regulation of PTBP1 and its associated signalling networks following H2O2-induced apoptosis in SH-SY5Y cells. B12 or related compounds may prove to be useful therapeutic agents for the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's.


Cyclooxygenase-2 inhibitor treatment of older osteoarthritis patients.
Nonsteroidal anti-inflammatory drugs are often prescribed to treat osteoarthritis. Two cyclooxygenase isoenzymes prompted the development selective COX-2 inhibitors. The development, efficacy, and toxicity of COX-2 inhibitor treatment of osteoarthritis are summarized.


Integration potential of mouse and human bone marrow-derived mesenchymal stem cells.
Mesenchymal stem cells (MSCs) are a multipotent cell population which has been described to exert renoprotective and regenerative effects in experimental models of kidney injury. Several lines of evidence indicate that MSCs also have the ability to contribute to nephrogenesis, suggesting that the cells can be employed in stem cell-based applications aimed at de novo renal tissue generation. In this study we re-evaluate the capacity of mouse and human bone marrow-derived MSCs to contribute to the development of renal tissue using a novel method of embryonic kidney culture. Although MSCs show expression of some genes involved in renal development, their contribution to nephrogenesis is very limited in comparison to other stem cell types tested. Furthermore, we found that both mouse and human MSCs have a detrimental effect on the ex vivo development of mouse embryonic kidney, this effect being mediated through a paracrine action. Stimulation with conditioned medium from a mouse renal progenitor population increases the ability of mouse MSCs to integrate into developing renal tissue and prevents the negative effects on kidney development, but does not appear to enhance their ability to undergo nephrogenesis.


Botulism among penned pheasants and protection by vaccination with C1 toxoid.
Fifty to 100 per cent of about 8000 penned pheasants raised on a farm in Hiroshima Prefecture died annually for three years. Deaths were ascribed to type C botulism. Vaccination of four groups of pheasants with partially purified C1 toxoid effectively protected them against type C botulism. The protective efficacy of the toxoid was emphasised by the relatively high susceptibility of the pheasant to C1 toxin.


APOE gene region methylation is associated with cognitive performance in middle-aged urban adults.
Apolipoprotein (APOE) ε4 allele is a strong risk factor for Alzheimer's disease (AD) and cognitive decline. Epigenetic modifications such as DNA methylation (DNAm) play a central role in cognition. This study sought to identify DNAm sites in the APOE genomic region associated with cognitive performance in a racially diverse middle-aged cohort (n = 411). Cognitive performance was measured by 11 standard neuropsychological tests. Two CpG sites were associated with the Card Rotation and Benton Visual Retention cognitive tests. The methylation level of the CpG site cg00397545 was associated with Card Rotation Test score (p = 0.000177) and a novel CpG site cg10178308 was associated with Benton Visual Retention Test score (p = 0.000084). Significant associations were observed among the dietary inflammatory index, which reflects the inflammatory potential of the diet, cognitive performance and the methylation level of several CpG sites. Our results indicate that DNAm in the APOE genomic area is correlated with cognitive performance and may presage cognitive decline.


Suprachoroidal drug delivery to the back of the eye using hollow microneedles.
In this work, we tested the hypothesis that microneedles provide a minimally invasive method to inject particles into the suprachoroidal space for drug delivery to the back of the eye. A single, hollow microneedle was inserted into the sclera, and infused nanoparticle and microparticle suspensions into the suprachoroidal space. Experiments were performed on whole rabbit, pig, and human eyes ex vivo. Particle delivery was imaged using brightfield and fluorescence microscopy as well as microcomputed tomography. Microneedles were shown to deliver sulforhodamine B as well as nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig, and human eyes. Volumes up to 35 μL were administered consistently. Optimization of the delivery device parameters showed that microneedle length, pressure, and particle size played an important role in determining successful delivery into the suprachoroidal space. Needle lengths of 800-1,000 μm and applied pressures of 250-300 kPa provided most reliable delivery. Microneedles were shown for the first time to deliver nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig and human eyes. This shows that microneedles may provide a minimally invasive method for controlled drug delivery to the back of the eye.


What's in a word? A parametric study of semantic influences on visual word recognition.
To what extent does semantic information play a functional role in visual word recognition? Theories of word recognition vary in the importance assigned to semantic information in visual lexical decision, with past research suggesting that the nature of the foils is a crucial determinant of semantic reliance. Here, we explored the conditions under which semantic variables influence lexical decision. Normal readers performed visual lexical decision tasks in which imageability and semantic priming were manipulated, with nonword foils varying systematically in their orthographic and phonological similarity to the real words. The effects of imageability and semantic priming increased in magnitude as nonword foils became progressively more wordlike. These findings provide a clear illustration of the flexible use of semantic information to support normal visual word recognition.


Gallic acid induces mitotic catastrophe and inhibits centrosomal clustering in HeLa cells.
Cancer cells divide rapidly, providing medical targets for anticancer agents. The polyphenolic gallic acid (GA) is known to be toxic for certain cancer cells. However, the cellular mode of action has not been elucidated. Therefore, the current study addressed a potential effect of GA on the mitosis of cancer cells. GA inhibited viability of HeLa cells in a dose-dependent and time-dependent manner. We could show, using fluorescence-activated cell sorting (FACS), that this inhibition was accompanied by elevated frequency of cells arrested at the G2/M transition. This cell-cycle arrest was accompanied by mitotic catastrophe, and formation of cells with multiple nuclei. These aberrations were preceded by impaired centrosomal clustering. We arrive at a model of action, where GA inhibits the progression of the cell cycle at the G2/M phase by impairing centrosomal clustering which will stimulate mitotic catastrophe. Thus, GA has potential as compound against cervical cancer.


Congenital aplasia of major salivary glands in a 4-year-old child.
The case of a 4-year-old girl with marked xerostomia and rampant caries is described. Investigation revealed complete aplasia of all four major salivary glands, which is extremely rare. Eleven primary teeth were extracted and a strict caries-preventive regime introduced. The patient had previously been advised to suck citrus-flavoured sweets to stimulate saliva flow, but this must be discouraged.


Second malignancy probabilities in patients with prostate cancer treated with whole pelvis radiation therapy versus prostate only radiation therapy.
Whole pelvic radiation therapy (WPRT) may improve outcomes compared with prostate only radiation therapy (PORT) in some subsets of men with prostate cancer, as in the POP-RT trial. However, there is concern about increased risk of adverse effects with WPRT, including the development of radiation-induced second malignancies (SM). Given the rarity of SM, little is known about relative rates of SM between WPRT and PORT. A retrospective cohort analysis was performed of men with nonmetastatic, node-negative prostate cancer with at least 60 months of follow-up using a national database. SM probabilities were compared in men receiving either WPRT or PORT using multivariable logistic models adjusting for clinical and sociodemographic factors. Temporal sensitivity analyses stratified by year of diagnosis and length of follow-up were also conducted. Of 50,237 patients in the study, 39,338 (78.4%) received PORT, and 10,899 (21.7%) received WPRT. Median follow-up was 106.2 months (interquartile range 82.32-132.25). Crude probabilities of SM were 9.16% for WPRT and 8.88% for PORT. The adjusted odds ratio (AOR) for development of SM with PORT versus WPRT was 1.046 (95% confidence interval 0.968-1.130). Temporal sensitivity analyses by stratifying by year of diagnosis and follow-up length also did not demonstrate any significant difference in rates of SM between WPRT and PORT using AORs with WPRT as the referent. Retrospective analysis of over 50,000 patients did not demonstrate an association between WPRT and an increased probability of SM compared to PORT. Given the findings of POP-RT, the use of WPRT may become widespread for certain subsets of men. Thus, our findings could help guide how we counsel patients deciding between WPRT and PORT and suggest the need for prospective assessment of SM risk with WPRT and PORT.


Adult live donor liver transplantation.
The increasing awareness of liver diseases and their early detection have led to an increase in the number of transplant waiting list candidates over the past decade. This need has not been matched by the actual number of orthotopic liver transplantations performed. Live donor liver transplantation (LDLT) is an innovative surgical technique intended to expand the available organ donor pool. Although LDLT offers definite advantages to the recipient, it offers none to the donor except for the possibility of psychological well-being. Clinical research studies aimed at the prospective collection of data for donors and recipients need to be conducted.


Novel Therapies in Myelofibrosis: Beyond JAK Inhibitors.
To discuss the current treatment paradigm, review novel targets, and summarize completed and ongoing clinical trials that may lead to a paradigm shifts in the management of myelofibrosis (MF). In addition to the recent approval and ongoing late-stage development of multiple novel JAK inhibitors, recent clinical studies demonstrate therapeutic potential of targeting multiple alternate proteins and pathways including BET, MDM2, telomerase, BCL2, LSD1, PI3K, SMAC, and PTX2 in patients with MF. MF is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells and bone marrow fibrosis often causing cytopenias, extramedullary hematopoiesis resulting in hepatosplenomegaly, and increased pro-inflammatory cytokine production driving systemic symptoms. A significant proportion of morbidity and mortality is related to the propensity to transform to acute leukemia. Allogeneic hematopoietic stem cell transplantation is the only curative therapy; however, due to the high associated mortality, this treatment is not an option for the majority of patients with MF. Currently, there are three targeted Food and Drug Administration (FDA)-approved therapies for MF which include ruxolitinib, fedratinib, and pacritinib, all part of the JAK inhibitor class. Many patients are unable to tolerate, do not respond, or develop resistance to existing therapies, leaving a large unmet medical need. In this review, we discuss the current treatment paradigm and novel therapies in development for the treatment of MF. We review the scientific rationale of each targeted pathway. We summarize updated clinical data and ongoing trials that may lead to FDA approval of these agents.


Grapevine trunk diseases associated with fungi from the Diaporthaceae family in Croatian vineyards.
Grapevine trunk diseases (GTD) have a variety of symptoms and causes. The latter include fungal species from the family Diaporthaceae. The aim of our study was to determine Diaporthaceae species present in the woody parts of grapevines sampled from 12 vine-growing coastal and continental areas of Croatia. The fungi were isolated from diseased wood, and cultures analysed for phenotype (morphology and pathogenicity) and DNA sequence (ITS1, 5.8S, ITS2). Most isolates were identified as Phomopsis viticola, followed by Diaporthe neotheicola and Diaporthe eres. This is the first report of Diaporthe eres as a pathogen on grapevine in the world, while for Diaporthe neotheicola this is the first report in Croatia. Pathogenicity trials confirmed Phomopsis viticola as a strong and Diaporthe neotheicola as a weak pathogen. Diaporthe eres turned out to be a moderate pathogen, which implies that the species could have a more important role in the aetiology of GTD.


Paracoccidioidomycosis.
Paracoccidioidomycosis is a fungal infection that is relatively common in Brazil, Venezuela, Colombia, Ecuador, and Argentina. Sporadic cases can also be seen in some other countries. It is caused by a dimorphic fungus, Paracoccidioides brasiliensis, which affects mainly the skin, lymph nodes, lungs, and oral, nasal, and gastrointestinal mucous membranes. Depending on the specific immunity of the host, the infection can assume many forms and affect single or multiple organs, eventually becoming a severe and even fatal disease. It is very important for dermatologists of all over the world to know about paracoccidioidomycosis because sometimes the disease only manifests many years after the individual has left the endemic area.


Efficacy and safety of selamectin against Sarcoptes scabiei on dogs and Otodectes cynotis on dogs and cats presented as veterinary patients.
A series of randomized, controlled and masked field studies was conducted in veterinary patients to evaluate the efficacy of selamectin, a novel avermectin, in the treatment of naturally occurring Sarcoptes scabiei infestations on dogs and Otodectes cynotis infestations on dogs and cats. A total of 342 dogs and 237 cats participated in these studies, which were conducted at 40 veterinary practices in the USA and Europe. Animals were randomly assigned to treatment with selamectin or a positive-control product (existing approved products). Selamectin was administered as a unit dose providing a minimum of 6mgkg(-1) (range: 6-12mgkg(-1)) in a topical preparation applied to the skin in a single spot on day 0 (O. cynotis in cats, n=144), or on days 0 and 30 (O. cynotis and S. scabiei in dogs, n=83 and n=122, respectively). The presence of parasites was assessed before treatment and at 30 days (for all studies) and 60 days (for O. cynotis and S. scabiei dog studies) after first treatment. The animals were also evaluated clinically at each assessment period. Based on skin scrapings, the efficacy of selamectin against S. scabiei infestations on dogs was >95% by day 30, and 100% by day 60. Against O. cynotis, selamectin eliminated mites in 94-100% of cats by day 30, and in 90% of dogs by day 60. The positive-control products achieved similar results. Thus, selamectin was safe and effective against ear mites in dogs and cats and sarcoptic mange in dogs when used in field (veterinary patient) studies in dogs and cats of a wide variety of ages and breeds.


Cerebellar Syndrome Induced by Hypomagnesemia: A Treatable Cause of Ataxia Not to be Missed. Report of Three Cases and a Review of the Literature.
Magnesium is an important intracellular cation involved in essential enzymatic reactions. It is necessary for neuronal function and its depletion can produce neurological symptoms such as cramps or seizures. Clinical consequences of its deficit in the cerebellum are less known and the diagnosis can be delayed because of the lack of awareness on this condition. We present three cases of cerebellar syndrome (CS) due to hypomagnesemia: A midline CS with myoclonus and ocular flutter and two cases of hemispheric CS, one of them entailed a Schmahmann's syndrome and the other suffered a seizure. MRI findings revealed cerebellar vasogenic edema and the symptoms improved after magnesium replacement in all cases. We reviewed 22 cases of CS due to hypomagnesemia, all with subacute onset (days to weeks). Encephalopathy and/or epileptic seizures were common. MRI findings were vasogenic edema involving the cerebellar hemispheres, the vermis, or the nodule. Up to 50% of patients presented hypocalcemia and/or hypokalemia. All the patients showed symptomatic improvement after magnesium replacement, but 50% showed significant sequelae, and 46% relapsed. Hypomagnesaemia should always be considered in the differential diagnosis of CS as it has a potential treatment, and its early recognition can avoid recurrences and permanent cerebellar impairment.


Vestibular activation, smooth pursuit tracking, and psychosis.
Pursuit tracking and vestibular activation procedures were combined in an investigation to determine if smooth pursuit tracking deficits could be related to abnormalities of visual-vestibular interaction in psychiatric patients. In actively psychotic patients, but not in comparison groups of schizophrenic outpatients with remitted symptomatology or normal controls, a significant failure of visual fixation to suppress caloric nystagmus was related to a higher incidence of disordered tracking during both baseline and postirrigation conditions. Other vestibular irregularities including dysrhythmia and reduced fast phase velocity were observed in these same patients. The results are supportive of a central deficit in visual-vestibular interaction that may contribute to pursuit tracking deficits in psychosis.


[Pharmacology and clinical relevance of vasopressin antagonists].
As vasopressin receptors are found in many different tissues, vasopressin antagonists may benefit the treatment of numerous disorders. Effects of vasopressin via V1(a) and V2 receptors are closely implicated in a variety of water-retaining diseases and cardiovascular diseases, including heart failure, hyponatremia, hypertension, renal diseases, syndrome of inappropriate antidiuretic hormone secretion, cirrhosis, and ocular hypertension. Furthermore, V1(a) vasopressin antagonists might be useful in cerebral ischemia and stroke, Raynaud's disease, dysmenorrhoea and tocolytic treatment. V1(b) selective vasopressin antagonists are discussed in terms of their usefulness in the treatment of emotional and psychiatric disorders. The vaptans are vasopressin receptor antagonists with V1(a) (relcovaptan) or V2 (tolvaptan, lixivaptan, satavaptan) selectivity or non-selective activity (conivaptan). Conivaptan is the first vaptan which has been approved by the FDA for the treatment of euvolemic hyponatremia. For further indications such as congenital heart failure, studies are going on.


General Movement Assessment in Babies Born Preterm: Motor Optimality Score-Revised (MOS-R), Trajectory, and Neurodevelopmental Outcomes at 1 Year.
To assess the association between the General Movement Assessment (GMA) findings, including Motor Optimality Scores-Revised (MOS-R) at 16 weeks, and neuromotor outcome assessed by the Amiel-Tison Neurological Assessment at 9 months of corrected age and the Developmental Assessment Scales for Indian Infants (DASII) at 1 year of corrected age in preterm ≤32 weeks. Serial GMA videos of infants born preterm ≤32 weeks were recorded on day 7, 35 weeks of postmenstrual age, 40 weeks of postmenstrual age, and 16 weeks of corrected age. The association between GMA findings, including MOS-R scores and GM trajectory between 35 to 40 weeks and the Amiel-Tison Neurological Assessment and DASII scores, was assessed by Spearman correlation, Fisher exact tests, and ordinal regression. Moderate correlations were observed between MOS-R and the DASII motor DQ (Spearman r = 0.70, P < .001) and between MOS-R and DASII Mental DQ (r = 0.65, P < .001). The GMA trajectory at 35-40 weeks was associated with DASII motor DQ (Fisher exact, P = .002), and also with the Amiel-Tison Neurological Assessment at 9 months of corrected age (P < .01 by the Fisher exact test). On analysis by performing ordinal regression of predictive values of the general movements (GM) at 7 days of age, GM at 35 weeks, GM at 40 weeks, GM at 16 weeks, and MOS-R at 16 weeks, MOS-R alone was a statistically significant predictor of motor DQ at 1 year of age (OR -0.59; 95% CI -0.97 to -0.22; Wald statistics, P < .02). Consistent with findings in high-income countries, GMA including MOS-R scores performed in Indian infants born preterm during the neonatal period and early infancy is associated with neurodevelopmental outcomes in the first year of life. GMA can help initiate focused early intervention in low- and middle-income settings, where resources may be limited.


A new deep learning approach integrated with clinical data for the dermoscopic differentiation of early melanomas from atypical nevi.
Timely recognition of malignant melanoma (MM) is challenging for dermatologists worldwide and represents the main determinant for mortality. Dermoscopic examination is influenced by dermatologists' experience and fails to achieve adequate accuracy and reproducibility in discriminating atypical nevi (AN) from early melanomas (EM). We aimed to develop a Deep Convolutional Neural Network (DCNN) model able to support dermatologists in the classification and management of atypical melanocytic skin lesions (aMSL). A training set (630 images), a validation set (135) and a testing set (214) were derived from the idScore dataset of 979 challenging aMSL cases in which the dermoscopic image is integrated with clinical data (age, sex, body site and diameter) and associated with histological data. A DCNN_aMSL architecture was designed and then trained on both dermoscopic images of aMSL and the clinical/anamnestic data, resulting in the integrated "iDCNN_aMSL" model. Responses of 111 dermatologists with different experience levels on both aMSL classification (intuitive diagnosis) and management decisions (no/long follow-up; short follow-up; excision/preventive excision) were compared with the DCNNs models. In the lesion classification study, the iDCNN_aMSL achieved the best accuracy, reaching an AUC = 90.3 %, SE = 86.5 % and SP = 73.6 %, compared to DCNN_aMSL (SE = 89.2 %, SP = 65.7 %) and intuitive diagnosis of dermatologists (SE = 77.0 %; SP = 61.4 %). The iDCNN_aMSL proved to be the best support tool for management decisions reducing the ratio of inappropriate excision. The proposed iDCNN_aMSL model can represent a valid support for dermatologists in discriminating AN from EM with high accuracy and for medical decision making by reducing their rates of inappropriate excisions.


Super-resolution imaging uncovers the nanoscopic segregation of polarity proteins in epithelia.
Epithelial tissues acquire their integrity and function through the apico-basal polarization of their constituent cells. Proteins of the PAR and Crumbs complexes are pivotal to epithelial polarization, but the mechanistic understanding of polarization is challenging to reach, largely because numerous potential interactions between these proteins and others have been found, without a clear hierarchy in importance. We identify the regionalized and segregated organization of members of the PAR and Crumbs complexes at epithelial apical junctions by imaging endogenous proteins using stimulated-emission-depletion microscopy on Caco-2 cells, and human and murine intestinal samples. Proteins organize in submicrometric clusters, with PAR3 overlapping with the tight junction (TJ) while PALS1-PATJ and aPKC-PAR6β form segregated clusters that are apical of the TJ and present in an alternated pattern related to actin organization. CRB3A is also apical of the TJ and partially overlaps with other polarity proteins. Of the numerous potential interactions identified between polarity proteins, only PALS1-PATJ and aPKC-PAR6β are spatially relevant in the junctional area of mature epithelial cells, simplifying our view of how polarity proteins could cooperate to drive and maintain cell polarity.


The effect of delaying radiation therapy for systemic chemotherapy on local-regional control in breast cancer.
It remains controversial as to whether the administration of chemotherapy prior to radiation following the surgical treatment for localized breast cancer compromises local control. The outcome of 290 patients who received chemotherapy prior to breast or chest wall irradiation following curative breast cancer surgery was retrospectively analyzed to determine if delaying radiation from the time of surgery adversely affects local-regional control. The patients were divided into three groups according to the time interval from definitive surgery to the start of radiation: group 1, < 5 months; group 2, 5 to < 7 months, and group 3, 7+ months. Local-regional and distant failure events were analyzed according to the time delay from surgery to radiation. The median follow-up was 6.0 years (range, 7 months to 15 years). Loco-regional failure was observed in 22 patients, 18 of which occurred within the original radiation fields. There was no significant adverse effect on local control or distant failure from delaying radiation for systemic chemotherapy. Univariate and multivariate analyses revealed that positive margins after surgery were associated with increased local recurrence. Delaying radiation therapy for greater than 7 months, in order to administer chemotherapy following curative breast cancer surgery, does not compromise local control. However, positive margins were significantly associated with higher rates of local failure and even an increase in radiation boost dose was not able to fully counteract the increased risk of local failure.


Lymphoid stroma of Warthin's tumor: phenotypic analogies with gut-associated lymphoid tissue.
Lymphocytes in cell suspensions and cryostat sections of Warthin's tumors (WT) have been phenotypically characterized using a battery of monoclonal and polyclonal antisera to lymphoid cell-associated antigens. The present study shows that in the WT lymphoid stroma, B cells are more numerous than T lymphocytes and include a significant percentage of surface immunoglobulin A-bearing cells. Of the T cells, the Leu 3a+ and OKT4+ lymphocytes are present in higher percentages than the OKT8+ ones. Both T-cell subsets present a topographic distribution which is similar to that found in human tonsils and gut tunica propria. Intraepithelial lymphocytes displaying an OKT8+, Leu 3a-, OKT3- phenotype are also present. These data, together with previous findings which have demonstrated that Warthin's tumor epithelium synthesizes IgA secretory piece, suggest that these cells may modulate the organization of the surrounding lymphoid stroma toward that of a mature lymphatic tissue phenotipically resembling gut-associated lymphoid tissue.


Augmentation of in vitro interleukin 10 production after in vivo administration of interleukin 18 is activated macrophage-dependent and is probably not involved in the antitumor effects of interleukin 18.
We have previously shown that interleukin (IL)-18 protects mice from intraperitoneal transplantation with syngeneic Meth A sarcoma, and in the process induces the production of large amounts of IL-10 from mitogen-stimulated treated mouse spleen cells, with a simultaneous augmentation of natural killer (NK) cell activity. Using in vivo and in vitro cell depletion methods, we now show that the cells producing IL-10 are neither NK cells nor macrophages (M phi), but that the IL-10 production is dependent on the presence of treated mouse M phi. Anti-IL-12 and anti-CD40L neutralizing antibodies could not inhibit the production of IL-10. Although IL-18-treated normal mouse enriched T cells stimulated with anti-CD3 and anti-CD28 antibodies failed to produce IL-10, the cytokine was also undetectable in culture supernatants of IL-18-treated nude mouse spleen cells, indicating that T cells were directly involved in the induced production of IL-10. Flow cytometry for intracellular IL-10 confirmed that CD8+ T cells and other, as yet unidentified spleen cell sub-sets were secreting IL-10, but only a small percentage of CD4+ cells produced IL-10. In vivo experiments using anti-IL-10 antibody indicated that IL-10 may not be directly involved in the antitumor effects of IL-18.


A polyacetylene compound from herbal medicine regulates genes associated with thrombosis in endothelial cells.
From Toki-shakuyaku-san, an herbal formulation for 'cleansing stagnated blood,' a key gene regulatory compound was purified and identified through a screening based on DNA microarray and real-time PCR.


Cannabinoids as Prospective Anti-Cancer Drugs: Mechanism of Action in Healthy and Cancer Cells.
Endogenous and exogenous cannabinoids modulate many physiological and pathological processes by binding classical cannabinoid receptors 1 (CB1) or 2 (CB2) or non-cannabinoid receptors. Cannabinoids are known to exert antiproliferative, apoptotic, anti-migratory and anti-invasive effect on cancer cells by inducing or inhibiting various signaling cascades. In this chapter, we specifically emphasize the latest research works about the alterations in endocannabinoid system (ECS) components in malignancies and cancer cell proliferation, migration, invasion, angiogenesis, autophagy, and death by cannabinoid administration, emphasizing their mechanism of action, and give a future perspective for clinical use.


A method comparison of photovoice and content analysis: research examining challenges and supports of family caregivers.
The purpose of this manuscript is to compare methods and thematic representations of the challenges and supports of family caregivers identified with photovoice methodology contrasted with content analysis, a more traditional qualitative approach. Results from a photovoice study utilizing a participatory action research framework was compared to an analysis of the audio-transcripts from that study utilizing content analysis methodology. Major similarities between the results are identified with some notable differences. Content analysis provides a more in-depth and abstract elucidation of the nature of the challenges and supports of the family caregiver. The comparison provides evidence to support the trustworthiness of photovoice methodology with limitations identified. The enhanced elaboration of theme and categories with content analysis may have some advantages relevant to the utilization of this knowledge by health care professionals.


Limitations of prostate specific antigen doubling time following biochemical recurrence after radical prostatectomy: results from the SEARCH database.
Prostate specific antigen doubling time following biochemical recurrence after radical prostatectomy is a powerful predictor of prostate cancer specific and overall death. To calculate prostate specific antigen doubling time requires multiple prostate specific antigen determinations that are unaltered by secondary therapy and separated by sufficient time. Physicians and patients may be unwilling to wait before starting secondary therapy, especially for high risk recurrences. Hence, those with calculable prostate specific antigen doubling time may represent a select lower risk group relative to all men with biochemical recurrence. We compared clinical and pathological features between patients with and without calculable prostate specific antigen doubling time. We assessed time trends in the proportion with calculable prostate specific antigen doubling time in 535 patients with biochemical recurrence after radical prostatectomy at 5 Veterans Affairs medical centers comprising the SEARCH (Shared Equal Access Regional Cancer Hospital) database between 1988 and 2003. Prostate specific antigen doubling time was not calculable in 187 patients (35%) due to secondary therapy in 155 (83%). With time the proportion of patients with calculable prostate specific antigen doubling time decreased significantly (p <0.001). Adverse pathological features, more rapid time to recurrence, higher body mass index and differing surgical centers were associated with not having a calculable prostate specific antigen doubling time. Of all men with recurrence in the most recent year of analysis the adjusted probability of having a calculable prostate specific antigen doubling time was only 43%, that is 61% in patients with favorable pathological results but only 30% in those with seminal vesicle invasion. Those with calculable prostate specific antigen doubling time represented a select, lower risk cohort and the proportion of patients with calculable prostate specific antigen doubling time decreased with time. This highlights the need for alternative markers in men with recurrent prostate cancer because one of our best current markers, prostate specific antigen doubling time, is only available in a limited number of patients.


Improved visual acuity and recognition time in nystagmus patients following four-muscle recession or Kestenbaum-Anderson procedures.
Many patients describe more rapid recognition of objects after surgical procedures for nystagmus; however, this "recognition time" is not reflected in the parameters typically studied in these patients. The purpose of this study is to assess the effect of nystagmus surgery on visual acuity and recognition time. In this prospective, interventional, comparative case series, patients with nystagmus were divided into two groups. group A (n = 13) underwent four-muscle retroequatorial recession; group B (n = 8) underwent the Kestenbaum-Anderson procedure. Visual acuity, binocularity, and recognition time were assessed before and after surgery. Recognition time was measured in a routine examination setting using specially designed software that controlled the time of appearance of optotypes in 0.1 second increments. A total of 21 patients were enrolled. The entire group experienced significant postoperative improvement in visual acuity (P = 0.002) and recognition time (P = 0.005). The mean improvement in recognition time was 0.3 seconds at maximum preoperative visual acuity level. A trend toward more improvement in group A than in group B was not statistically significant. Both the four-muscle recession and the Kestenbaum-Anderson procedures resulted in a 1- to 2-line improvement in visual acuity and a 0.3 second improvement in optotype recognition time.


Effects of fixed appliances in correcting Angle Class II on the depth of the posterior airway space: FMA vs. Herbst appliance--a retrospective cephalometric study.
The objective of this retrospective study based on the metric evaluation of lateral cephalograms was to investigate the extent to which treatment with two different fixed appliances for the correction of Angle Class II influenced the morphology of the extrathoracic airway space (the posterior airway space, PAS). A total of 43 patients with Angle Class II malocclusion were classified into two groups according to the appliance used for treatment: the functional mandibular advancer (FMA; n = 18) or the Herbst appliance (n = 25). Lateral cephalograms were taken of each patient at the start of functional jaw orthopedic treatment (time point T1) and at its completion (time point T2). Specific distances and angles were measured and analyzed in a cephalometric analysis. We observed major differences among the 43 patients in the depth of the posterior airway space during treatment with fixed appliances for Angle Class II correction. Regression analysis revealed that changes in sagittal and vertical positions had different effects on the depth of specific PAS sections: increases in anterior facial height are associated proportionately with increases in PAS width, particularly in the upper region. On the other hand, increases in posterior facial height and in the mandible's forward displacement correlated inversely to the decreases in depth, particularly in the central and lower PAS regions. The two treatment appliances (FMA, Herbst appliance) had the same effects on extrathoracic airway depth. Analyses of lateral cephalograms indicate that Angle Class II treatment with fixed appliances does not prevent sleep apnea in patients at risk. Nevertheless, this study does not permit absolutely reliable conclusions about the dimensions of the pharyngeal airway space. As the lateral cephalogram provides good images of structures in the midsagittal plane but is incapable of imaging the transverse dimension, there is an automatic lack of information concerning the precise width and volume of the extrathoracic airway space.


Enhanced isobutanol production by co-production of polyhydroxybutyrate and cofactor engineering.
Once cells have been used to produce biochemicals, there are only a few effective ways to utilize the residual cell mass, even though the utilization of leftover cells would aid in decreasing production costs. Here, a polyhydroxybutyrate (PHB) and isobutanol co-production system was designed to address this challenge. The addition of the PHB operon into Escherichia coli conferred a metabolic advantage for alcohol production, generating 1.14-fold more isobutanol. Furthermore, following nitrogen source optimization and cofactor engineering, the engineered E. coli strain produced 2-fold more isobutanol and 0.25 g/L PHB. Moreover, E. coli cells showed higher tolerance to isobutanol with the overexpression of PHB biosynthesis genes. This co-production system resulted in an increased biomass, higher glucose utilization, and lower acetate maintenance, leading to higher productivity regarding PHB and isobutanol yield. Thus, this novel system is applicable to future fermentation studies for the co-production of PHB and isobutanol.


Antibacterial and anti-quorum sensing activities of a substituted thiazole derivative against methicillin-resistant Staphylococcus aureus and other multidrug-resistant bacteria.
Management of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) is still challenging. We herein report the antibacterial and anti-quorum sensing (anti-QS) activities of 5-acetyl-4-methyl-2-(3-pyridyl) thiazole (AMPT) against MRSA and other multidrug-resistant bacteria. Minimum inhibitory concentrations (MICs) were determined by agar dilution method and bactericidal activity was assessed by a time-kill assay. The anti-QS activity was evaluated using Chromobacterium violaceum. The effect of AMPT on virulence factors production by MRSA and biofilm formation by MRSA, C. violaceum and Pseudomonas aeruginosa was also assessed. AMPT was superior to vancomycin and teichoplanin against MRSA isolates. MIC50/90 values of AMPT (2/4 mg/L) were 2-4 folds lower than the values for vancomycin (4/16 mg/L) and 2-fold lower than the values for teichoplanin (4/8 mg/L). Results of time-kill assay against two multidrug-resistant MRSA isolates revealed bactericidal effect of AMPT after 4 h of treatment, with no bacterial cells detected after 24 h. Remarkably, AMPT exhibited anti-QS activity against both C. violaceum and MRSA at subinhibitory concentrations. Moreover, AMPT reduced haemolysin and protease production by MRSA and inhibited biofilm formation by MRSA, C. violaceum and P. aeruginosa but had no dispersion effect on preformed ones. Furthermore, molecular docking analysis revealed promising interactions between AMPT and AgrA as well as SarA in S. aureus confirming the antivirulence and antibiofilm activities. Favourably, no significant cytotoxicity of AMPT was observed on murine macrophage cell line. Taken altogether, these results suggest that AMPT could be considered an interesting lead compound in the search for treatment of MRSA infections.


Efficient iron single-atom catalysts for selective ammoxidation of alcohols to nitriles.
Zeolitic imidazolate frameworks derived Fe1-N-C catalysts with isolated single iron atoms have been synthesized and applied for selective ammoxidation reactions. For the preparation of the different Fe-based materials, benzylamine as an additive proved to be essential to tune the morphology and size of ZIFs resulting in uniform and smaller particles, which allow stable atomically dispersed Fe-N4 active sites. The optimal catalyst Fe1-N-C achieves an efficient synthesis of various aryl, heterocyclic, allylic, and aliphatic nitriles from alcohols in water under very mild conditions. With its chemoselectivity, recyclability, high efficiency under mild conditions this new system complements the toolbox of catalysts for nitrile synthesis, which are important intermediates with many applications in life sciences and industry.


Pulmonary vascular permeability index and global end-diastolic volume: are the data consistent in patients with femoral venous access for transpulmonary thermodilution: a prospective observational study.
Transpulmonary thermodilution (TPTD) derived parameters are used to direct fluid management in ICU-patients. Extravascular lung water EVLW and its ratio to pulmonary blood volume (pulmonary vascular permeability index PVPI) have been associated with mortality. In single indicator TPTD pulmonary blood volume (PBV) is estimated to be 25% of global end-diastolic volume (GEDV). A recent study demonstrated marked overestimation of GEDV indexed to body-surface area (BSA; GEDVI) when using a femoral central venous catheter (CVC) for indicator injection due to the additional volume measured in the vena cava inferior. Therefore, a correction formula derived from femoral TPTD and biometric data has been suggested. Consequence, one of the commercially available TPTD-devices (PiCCO; Pulsion Medical Systems, Germany) requires information about CVC site. Correction of GEDVI for femoral CVC can be assumed. However, there is no data if correction also pertains to unindexed GEDV, which is used for calculation of PBV and PVPI. Therefore, we investigated, if also GEDV, PBV and PVPI are corrected by the new PiCCO-algorithm. In this prospective study 110 triplicate TPTDs were performed within 30 hours in 11 adult ICU-patients with PiCCO-monitoring and femoral CVC. We analyzed if the femoral TPTD correction formula for GEDVI was also applied to correct GEDV. Furthermore, we compared PVPIdisplayed to PVPIcalculated which was calculated as EVLWdisplayed/(0.25*GEDVdisplayed). Multiplication of GEDVIdisplayed by BSA resulted in GEDVcalculated which was not significantly different to GEDVdisplayed (1459 ± 365 mL vs. 1459 ± 366 mL) suggesting that correction for femoral indicator injection also pertains to GEDVdisplayed. However, PVPIdisplayed was significantly lower than PVPIcalculated (1.64 ± 0.57 vs. 2.27 ± 0.72; p < 0.001). In addition to a bias of -0.64 ± 0.22 there was a percentage error of 22%. Application of the correction formula suggested for GEDVI to PVPIdisplayed reduced the bias of PVPIdisplayed compared to EVLW/PBV from -0.64 ± 0.22 to -0.10 ± 0.05 and the percentage error from 22% to 4%. Correction for femoral CVC in the PiCCO-device pertains to both GEDVIdisplayed and GEDVdisplayed, but not to PVPIdisplayed. To provide consistent information, PVPI should be calculated based on GEDVcorrected in case of femoral CVC.


Neurobehavioral effects of chronic halothane exposure during developmental and juvenile periods in the rat.
Chronic exposure of rats to the surgical anesthetic agent halothane during development has been found to cause both neural and behavioral impairment. Among the halothane-induced deficits are retarded synaptogenesis and impaired spontaneous alternation. It is unclear how long after birth the susceptibility to the neurotoxic effects of halothane persists. The present study compared in rats the effects of halothane exposure on synaptic density and spontaneous alternation during early and late periods of maturation. All three experimental groups were exposed to 100 parts per million of halothane for 8 h/day, 5 days/week. One group (early exposure) was exposed from day 2 of conception until 30 days after birth. The second group (late exposure) was exposed to the same amounts from day 31 until day 90 after birth. The third group (continued exposure) received both periods. The control group was treated in the same way, but was not exposed to halothane. As found in the previous study, there were greater effects of halothane on synaptogenesis than on spontaneous alternation; impairment of spontaneous alternation behavior was found only with the early exposure. Deficits in synaptic density were found with both early and late exposure, although the early exposure had more severe effects. Halting the exposure to halothane on day 30 reinstated control-like rates of synaptogenesis, but the deficit in synaptic density from the early exposure persisted into adulthood. The potent neurotoxic effect of halothane in suppressing synaptogenesis highlights not only its potential as a hazard but also its potential as an experimental tool for manipulating the rate of synaptogenesis and examining the relationship between synaptic development and behavioral maturation.


Current status of ischemic stroke treatment: From thrombolysis to potential regenerative medicine.
Ischemic stroke is a major cause of death and disability worldwide and is expected to increase in the future with the aging population. Currently, there are no clinically available treatments for damage sustained during an ischemic stroke, but much research is being conducted in this area. In this review, we will introduce current ischemic stroke treatments along with their limitations, as well as research on potential short and long-term future treatments. There are advantages and disadvantages in these potential treatments, but our understanding of these methods and their effectiveness in clinical trials are improving. We are confident that some future treatments introduced in this review will become commonly used in clinical settings in the future.


Overexpression of LHCSR and PsbS enhance light tolerance in Chlamydomonas reinhardtii.
Nonphotochemical quenching (NPQ) is a crucial mechanism for fine-tuning light harvesting and protecting the photosystem II (PSII) reaction centres from excess light energy in plants and algae. This process is regulated by photoprotective proteins LHCSR1, LHCSR3, and PsbS in green algae, such as Chlamydomonas reinhardtii. The det1-2 phot mutant, which overexpresses these photoprotective proteins, resulting in a significantly higher NPQ response, has been recently discovered in C. reinhardtii. Here, we analysed the physiological impact of this response on algal cells and found that det1-2 phot was capable of efficient growth under high light intensities, where wild-type (WT) cells were unable to survive. The mutant exhibited a smaller PSII cross-section in the dark and showed a detachment of the peripheral light-harvesting complex II (LHCII) antenna in the NPQ state, as suggested by a rise in the chlorophyll fluorescence parameter of photochemical quenching in the dark (qPd > 1). Furthermore, fluorescence decay-associated spectra demonstrated a decreased excitation pressure on PSII, with excess energy being directed toward PSI. The amount of LHCSR1, LHCSR3, and PsbS in the mutant correlated with the magnitude of the protective NPQ response. Overall, the study suggests the mechanism by which the overexpression of photoprotective proteins in det1-2 phot brings about an efficient and effective photoprotective response, enabling the mutant to grow and survive under high light intensities that would otherwise be lethal for WT cells.


Knowledge Attitude and Practice (KAP) survey among healthcare professionals in pediatrics on the psychomotor development of children. Case of urban and rural health areas in South Kivu in the Democratic Republic of Congo: a cross-sectional study.
Development refers to change. The study of development is the understanding of how a subject functions at a particular age or time in life. The objective of this study was to evaluate the knowledge, attitude, and practice of pediatric healthcare personnel on the psychomotor development of the child. This was a cross-sectional study of knowledge, attitude, and practice conducted in the health areas of South Kivu. Twenty-six caregivers participated in the survey. Men were the most represented (61.5%), mean age 27.62±5.07 years; median experience in pediatrics: 1 year; predominantly urban setting with 69.2%. General practitioners were more represented, with 57.7%. The overall state of knowledge was insufficient in 69.2%. Knowledge1 improves with increasing experience in pediatrics (P=0.008), and qualification improves knowledge1 (P=0.033) and knowledge3 (P=0.009). Knowledge4 improved from rural to urban settings (P=0.022).A good knowledge of the scales used in the evaluation of psychomotor development influences the use of one or the other (P=0.000). The authors also notice that those who indicate and/or have physical therapy practiced in rehabilitation are generally those who have a good knowledge of the use of psychomotor development assessment tools (P=0.010). This study highlights the low theoretical knowledge of caregivers on psychomotor development in our study setting, resulting in late diagnosis and consequently poor treatment of psychomotor development disorders. The results of this study indicate a need for continuing education for pediatric caregivers on the psychomotor development of the child.


Aggregatibacter actinomycetemcomitans induces detachment and death of human gingival epithelial cells and fibroblasts via elastase release following leukotoxin-dependent neutrophil lysis.
Aggregatibacter actinomycetemcomitans is considered to be associated with periodontitis. Leukotoxin (LtxA), which destroys leukocytes in humans, is one of this bacterium's major virulence factors. Amounts of neutrophil elastase (NE), which is normally localized in the cytoplasm of neutrophils, are reportedly increased in the saliva of patients with periodontitis. However, the mechanism by which NE is released from human neutrophils and the role of NE in periodontitis is unclear. In the present study, it was hypothesized that LtxA induces NE release from human neutrophils, which subsequently causes the breakdown of periodontal tissues. LtxA-treatment did not induce significant cytotoxicity against human gingival epithelial cells (HGECs) or human gingival fibroblasts (HGFs). However, it did induce significant cytotoxicity against human neutrophils, leading to NE release. Furthermore, NE and the supernatant from LtxA-treated human neutrophils induced detachment and death of HGECs and HGFs, these effects being inhibited by administration of an NE inhibitor, sivelestat. The present results suggest that LtxA mediates human neutrophil lysis and induces the subsequent release of NE, which eventually results in detachment and death of HGECs and HGFs. Thus, LtxA-induced release of NE could cause breakdown of periodontal tissue and thereby exacerbate periodontitis.


Sources of prescription opioids and tranquilizers for misuse among U.S. young adults: differences between high school dropouts and graduates and associations with adverse outcomes.
Background and Objectives: Prior research has identified that sources of prescription drugs for misuse vary based on educational attainment, which is important as certain sources are associated with adverse outcomes. The current research addressed limitations of the extant literature by creating distinct categories of push factors for high school dropout (e.g., negative school performance/experiences), pull factors for high school dropout (e.g., starting a family or getting a job), and high school graduates who did not attend college.Methods: Using data from the 2009-2014 National Survey on Drug Use and Health, prevalence of sources were estimated and design-based multivariable logistic regression investigated the association between sources and educational attainment. Additionally, multivariable logistic regression assessed the associations between sources and adverse outcomes (i.e., substance use, substance use disorders, and mental health) separately for each educational category.Results: College respondents were more likely to report "physician" and free from "friend/relative" and less likely to report "purchased" as sources. For most educational categories, "purchasing" prescription drugs was associated with adverse outcomes. Additionally, "theft/fake" prescription emerged as a source associated with adverse outcomes for college respondents, while "friend/relative" was associated with adverse outcomes for high school graduates that did not go on to college.Conclusions: This research has important clinical implications as it identified young adults with a college education as being less likely to obtain prescription drugs from sources known to be associated with adverse outcomes. It also highlighted how associations between sources and adverse outcomes vary based on educational attainment.


METTL3 promotes prostatic hyperplasia by regulating PTEN expression in an m6A-YTHDF2-dependent manner.
Uncontrolled epithelial cell proliferation in the prostate transition zone and the hyper-accumulation of mesenchymal-like cells derived from the epithelial-mesenchymal transition (EMT) of prostatic epithelium are two key processes in benign prostatic hyperplasia (BPH). m6A RNA modification affects multiple cellular processes, including cell proliferation, apoptosis, and differentiation. In this study, the aberrant up-regulation of methylase METTL3 in BPH samples suggests its potential role in BPH development. Elevated m6A modification in the prostate of the BPH rat was partially reduced by METTL3 knockdown. METTL3 knockdown also partially reduced the prostatic epithelial thickness and prostate weight, significantly improved the histological features of the prostate, inhibited epithelial proliferation and EMT, and promoted apoptosis. In vitro, METTL3 knockdown decreased TGF-β-stimulated BPH-1 cell proliferation, m6A modification, and EMT, whereas promoted cell apoptosis. METTL3 increased the m6A modification of PTEN and inhibited its expression through the reading protein YTHDF2. PTEN knockdown aggravated the molecular, cellular, and pathological alterations in the prostate of BPH rats and amplified TGF-β-induced changes in BPH-1 cells. More importantly, PTEN knockdown partially abolished the improving effects of METTL3 knockdown both in vivo and in vitro. In conclusion, the level of m6A modification is elevated in BPH; the METTL3/YTHDF2/PTEN axis disturbs the balance between epithelial proliferation and apoptosis, promotes EMT, and accelerates BPH development in an m6A modification-related manner.


[Allergic immunotherapy in children and adolescents].
Specific allergic immunotherapy requires repeated administration of allergens in order to induce clinical and immunological tolerance. This is the only therapy with an aetiological aim that modifies the course of the disease by ensuring remission after the interruption of the procedure. The prevention of new sensitizations by immunotherapy is still under discussion. In this review we will consider the main immunological mechanisms and indications for immunotherapy in children and adolescents.


Effect of early determinants on adolescent fat-free mass: RPS cohort of São Luís - MA.
To analyze the effects of early determinants on adolescent fat-free mass. A cohort study with 579 adolescents evaluated at birth and adolescence in a birth cohort in São Luís, Maranhão. In the proposed model, estimated by structural equation modeling, socioeconomic status (SES) at birth, maternal age, pregestational body mass index (BMI), gestational smoking, gestational weight gain, type of delivery, gestational age, sex of the newborn, length and weight at birth, adolescent socioeconomic status, "neither study/nor work" generation, adolescent physical activity level and alcohol consumption were tested as early determinants of adolescent fat-free mass (FFM). A higher pregestational BMI resulted in higher FFM in adolescence (Standardized Coefficient, SC = 0.152; p < 0.001). Being female implied a lower FFM in adolescence (SC = -0.633; p < 0.001). The negative effect of gender on FFM was direct (SC = -0.523; p < 0.001), but there was an indirect negative effect via physical activity level (SC = -0.085; p < 0.001). Women were less active (p < 0.001). An increase of 0.5 kg (1 Standard Deviation, SD) in birth weight led to a gain of 0.25 kg/m2 (0.106 SD) in adolescent FFM index (p = 0.034). Not studying or working had a negative effect on the adolescent's FFM (SC = -0.106; p = 0.015). Elevation of 1 SD in the adolescent's physical activity level represented an increase of 0.5 kg/m2 (0.207 SD) in FFM index (p < 0.001). The early determinants with the greatest effects on adolescent FFM are gender, adolescent physical activity level, pregestational BMI, birth weight and belonging to the "neither-nor" generation.


Detection of Ehrlichia muris DNA from sika deer (Cervus nippon yesoensis) in Hokkaido, Japan.
Ehrlichia muris DNA was detected in the blood of sika deer (Cervus nippon yesoensis) by species-specific PCR based on the citrate synthase gene, which was shown to be more sensitive than species-specific PCR based on the 16S rRNA gene. Among 102 deer examined, one deer was positive. Deer may be a possible mammalian reservoir of E. muris.


Low Intensity Epicardial Pacing During the Absolute Refractory Period Augments Left Ventricular Function Mediated by Local Catecholamine Release.
Biventricular epicardial (Epi) pacing can augment left ventricular (LV) function in heart failure. We postulated that these effects might involve catecholamine release from local autonomic nerve activation. To evaluate this hypothesis we applied low intensity Epi electrical stimuli during the absolute refractory period (ARP), thus avoiding altered activation sequence. Anesthetized pigs (n = 6) were instrumented with an LV pressure (LVP) transducer, left atrial (LA) and LV Epi pacing electrodes, and sonomicrometer segment length (SL) gauges placed proximal and remote to the LV stimulation site. A catheter was placed into the great cardiac vein adjacent to the LV pacing site for norepinephrine (NE) analysis. During LA pacing at constant rate, 3 pulses (0.8 milliseconds, 2-3x threshold) were applied to the LV Epi electrodes during the ARP. An experimental run consisted of baseline, stimulation (10 minutes), and recovery (5 minutes), repeated 3 times before and after β1 - receptor blockade (BB, metoprolol). ARP stimulation produced significant increases in cardiac function reflected by elevated LVP, LV, dP/dtmax , and reduced time to LV dP/dtmax . This was accompanied by increased coronary NE levels and increases in LVP versus SL loop area in the remote myocardial segment. In contrast, the proximal segment exhibited early shortening and decreased loop area. BB abolished the changes in SL and LV function despite continued NE release. These results demonstrate that ARP EPI stimulation induces NE release mediating augmented global LV function. This effect may contribute to the beneficial effect of biventricular Epi pacing in heart failure in some patients.


Cytochrome c peroxidase activity of heme bound amyloid β peptides.
Heme bound amyloid β (Aβ) peptides, which have been associated with Alzheimer's disease (AD), can catalytically oxidize ferrocytochrome c (Cyt c(II)) in the presence of hydrogen peroxide (H2O2). The rate of catalytic oxidation of Cyt(II) c has been found to be dependent on several factors, such as concentration of heme(III)-Aβ, Cyt(II) c, H2O2, pH, ionic strength of the solution, and peptide chain length of Aβ. The above features resemble the naturally occurring enzyme cytochrome c peroxidase (CCP) which is known to catalytically oxidize Cyt(II) c in the presence of H2O2. In the absence of heme(III)-Aβ, the oxidation of Cyt(II) c is not catalytic. Thus, heme-Aβ complex behaves as CCP.


[Determination of deoxynivalenol in bread and beer].
Analytical procedures for the determination of deoxynivalenol (DON) in bread and beer, using enzyme immunoassay (EIA) and HPLC methods, were developed. For determination of DON by EIA, aqueous raw extracts of bread or degassed beer were extracted by liquid-liquid partitioning with ethyl acetate, the organic solvent evaporated, and the residue redissolved in phosphate buffered saline (PBS) for analysis. For determination by HPLC (UV detection at 218 nm), DON in bread extracts or beer was purified on immunoaffinity chromatographic columns. In bread, detection limits for DON of 15 µg/kg (EIA) and 7 µg/kg (HPLC) were achieved, with mean recoveries of 81%. In beer, the detection limit for DON was 2 µg/l both in EIA and HPLC, with recoveries of 91-93%. Both methods showed good agreement of the results for naturally contaminated sample materials, with r(2)=0.993 for bread and r(2)=0.823 for beer, respectively.


The Combined "Double-Pulley" Simple Knot Technique for Arthroscopic Transtendon Fixation of Partial Articular-Sided Tear of the Subscapularis Tendon.
Subscapularis tendon tears occur more frequently than previously suspected. Most subscapularis tendon tears are partial tears that have the potential to progress to complete tears. Repairs of partial tears of the tendon are performed to preserve normal shoulder function. This report describes a combined transtendon double-pulley and simple knot technique for repair of partial articular tears of the subscapularis tendon. This technique incorporates the advantages of transtendon repair, the double-pulley technique, and simple knot fixation.


DMMAN: A two-stage audio-visual fusion framework for sound separation and event localization.
Videos are used widely as the media platforms for human beings to touch the physical change of the world. However, we always receive the mixed sound from the multiple sound objects, and cannot distinguish and localize the sounds as the separate entities in videos. In order to solve this problem, a model named the Deep Multi-Modal Attention Network (DMMAN), is established to model the unconstrained video datasets for further finishing the sound source separation and event localization tasks in this paper. Based on the multi-modal separator and multi-modal matching classifier module, our model focuses on the sound separation and modal synchronization problems using two stage fusion of the sound and visual features. To link the multi-modal separator and multi-modal matching classifier modules, the regression and classification losses are employed to build the loss function of the DMMAN. The estimated spectrum masks and attention synchronization scores calculated by the DMMAN can be easily generalized to the sound source and event localization tasks. The quantitative experimental results show the DMMAN not only separates the high quality of the sound sources evaluated by Signal-to-Distortion Ratio and Signal-to-Interference Ratio metrics, but also is suitable for the mixed sound scenes that are never heard jointly. Meanwhile, DMMAN achieves better classification accuracy than other contrast baselines for the event localization tasks.


Effect of adjuvant frequency-specific microcurrents on pain and disability in patients treated with physical rehabilitation for neck and low back pain.
To evaluate the efficacy of adjuvant frequency-specific microcurrent (FSM) application on pain and disability in patients treated with physical rehabilitation for mechanical low back pain (LBP) and neck pain (NP). In this retrospective case-control study, pre- and post-treatment numerical pain rating scale (NPRS) score, Oswestry disability index (ODI) score, neck disability index (NDI) score, disability categories, and treatment outcome categories were compared between 213 patients in the FSM group (167 patients with LBP, 46 patients with NP) and 78 patients in the control group (61 patients with LBP, 17 patients with NP). In LBP patients, mean post-treatment NPRS score was significantly lower (p = 0.02) and a significantly higher percentage of patients were in the ≤3 NPRS score (p = 0.02), in the minimal disability (p = 0.01), and the full success (p = 0.006) categories post-treatment in the FSM group when compared to the control group. In NP patients, there was no significant difference in the post-treatment pain intensity, disability or treatment outcome when the 2 groups were compared. The use of adjuvant FSM application in patients treated with physical rehabilitation for LBP significantly improved pain and disability when compared to patients in the control group. Frequency specific microcurrent could be a useful adjuvant in the rehabilitation treatment of patients with low back pain.


Medical educators' perspectives of teaching physical examinations using ultrasonography at the undergraduate level.
Ultrasonography is increasingly used for teaching physical examination in medical schools. This study seeks the opinions of educators as to which physical examinations would be most enhanced by the addition of ultrasonography. We also asked when ultrasound-aided physical examination teaching could have deleterious effects if used outside its intended scope. All of the educators from the University of Calgary Master Teacher Program were invited to complete a 22-item paper-based survey. Survey items were generated independently by two investigators, with input from an expert panel (n = 5). Of the 36 educators, 27 (75%) completed the survey. Examinations identified to be potentially most useful included: measuring the size of the abdominal aorta, identifying the presence/absence of ascites, identifying the presence/absence of pleural effusions, and measuring the size of the bladder. Examinations thought to be potentially most harmful included: identifying the presence/absence of intrauterine pregnancy, measuring the size of the abdominal aorta, and identifying the presence/absence of pericardial effusion. Examinations that are potentially the most useful may also be potentially the most harmful. When initiating an ultrasound curriculum for physical examinations, educators should weigh the risks and benefits of examinations chosen.


[Three Years Follow-up Study after Refractive Small Incision Lenticule Extraction (SMILE) Using 500 kHz Femtosecond Laser in "Fast Mode"].
Background The aim of this clinical trial was to check the results of laser built-in settings 3 years after ReLEx SMILE for moderate and high myopia in unselected "real life" patients. Patients and Methods 50 myopic eyes of 27 patients were called in for examination after 3 years. 25 of these eyes with a preoperative myopia under - 6D comprised the "moderate myopia subgroup". All surgeries were performed with the 500 kHz VisuMax® femtosecond laser (Carl Zeiss Meditec AG, Jena) in the "fast mode" setting. Results The spherical equivalent (SE) of the entire group changed from - 6.18 D (± 1.91) prior to surgery to - 0.18 D (± 0.39) 3 years later. The preoperative SE in the moderate myopia subgroup changed from - 4.71 D (± 0.94) to - 0.04 D (± 0.23). 14 % of 50 eyes gained one line and 22 % lost one line of CDVA. The regression between month 3 and 36 was 0.07D for the entire group and 0.06 D for the moderate myopia subgroup. There were no late side effects. Primary undercorrection was predominantly seen in eyes over - 6 D. Conclusion ReLEx SMILE shows remarkable stability over the entire range of myopias after 3 years, however primary undercorrection occurs predominantly in eyes of - 6.0 D, which necessitates nomogram adjustment.


Value of Targeted Biopsies and Combined PSMA PET/CT and mp-MRI Imaging in Locally Recurrent Prostate Cancer after Primary Radiotherapy.
Radiorecurrent prostate cancer is conventionally confirmed using systematic and/or targeted biopsies. The availability of multiparametric (mp) MRI and prostate specific membrane antigen (PSMA) PET/CT has increased diagnostic accuracy. The objective was to determine the positive predictive value (PPV) of combined mp-MRI and PSMA PET/CT and whether pathology verification with MR-targeted biopsies remains necessary for patients with radiorecurrent prostate cancer. Patients with locally recurrent prostate cancer who were referred for 19 Gy single-dose MRI-guided focal salvage high dose rate (HDR) brachytherapy between 2015 and 2018 were included in the current analysis. Patients were selected if they underwent pre-biopsy mp-MRI and PSMA PET/CT. Based on these images, lesions suspect for isolated tumor recurrence were transperineally biopsied using transrectal ultrasound fused with MRI. A total of 41 patients were identified from the database who underwent cognitive targeted (n = 7) or MRI/PSMA-transrectal ultrasound (TRUS) fused targeted (n = 34) biopsies. A total of 40 (97.6%) patients had positive biopsies for recurrent cancer. Five patients initially had negative biopsies (all MRI/PSMA-TRUS fusion targeted), four of whom recurrence was confirmed after a re-biopsy. One (2.4%) patient refused re-biopsy, leading to a positive predictive value (PPV) for combined imaging of 97.6%. Biopsies can therefore safely be withheld when the results of the combined mp-MRI and PSMA PET/CT are conclusive, avoiding an unnecessary invasive and burdensome procedure.


Cold shock induces novel nuclear bodies in Xenopus oocytes.
Here we describe novel spherical structures that are induced by cold shock on the lampbrush chromosomes (LBCs) of Xenopus laevis oocytes. We call these structures cold bodies or C-bodies. C-bodies are distributed symmetrically on homologous LBCs, with a pattern similar to that of 5S rDNA. Neither active transcription nor translation is necessary for their formation. Similar protrusions occur on the edges of some nucleoli. Endogenous LBCs as well as those derived from injected sperm form C-bodies under cold shock conditions. The function of C-bodies is unknown.


Minimum optimum scale of federally qualified health maintenance organizations.
From a policy standpoint it is important to identify the level of output at which average cost per unit is at its lowest. If minimum optimum scale is achieved at a very high output level, it would suggest that monopoly conditions should be allowed to prevail. If, however, minimum optimum scale is achieved at a low level of output, more organizations would be able to survive, allowing for competition in the marketplace. Using data published by the Office of Health Maintenance Organizations, the relationship between size and average cost was examined in federally qualified staff, group, and Independent Practice Association (IPA) health maintenance organizations (HMOs) and minimum optimum scale was identified for each organization. The findings support the hypothesis that least cost size is achieved at the lowest level of output in IPA HMOs. The hypothesis that minimum optimum scale would be achieved at a lower level of output in group rather than in staff HMOs was not supported. This may be due to the practice of some staff HMOs of employing part-time, salaried providers and purchasing unique services from other providers.


Predictors of Ventriculostomy-Associated Infections: A Retrospective Study of 243 Patients.
Risk factors of ventriculostomy-associated infection (VAI) reported in the literature are variable owing to heterogeneity of external ventricular drainage (EVD) procedures and management. This study aimed to assess the rate of VAI and its risk factors. The medical records of patients >18 years old who received EVD catheterizations between January 2015 and December 2020 were retrospectively reviewed. Among 243 patients with 355 catheters, 23 VAIs were identified, yielding VIA rates of 9.5% per patient and 6.5% per catheter. VAI was associated with a longer total EVD duration (29.2 days vs. 15.8 days, P < 0.001), a longer procedural time (72 minutes vs. 41 minutes, P < 0.001), intraoperative ventriculostomy (39.1% vs. 9.1%, P < 0.001), craniotomy (87.0% vs. 60.9%, P = 0.014), and other systemic infections (30.4% vs. 8.2%, P = 0.004). On multivariate analysis, a longer total EVD duration (odds ratio 1.086, P < 0.001), intraoperative ventriculostomy (odds ratio 6.119, P = 0.001), and other systemic infections (odds ratio 4.620, P = 0.015) were associated with VAI. There was no statistical difference between the VAI rates of patients with and without prophylactic EVD exchanges at a mean 12.6 days (7.1% vs. 2.2%, P = 0.401). Intraoperative ventriculostomy was independently associated with VAI. Prophylactic EVD exchange at 12.6 days did not lower VAI rate.


In-vitro anti-cholinesterase activity of essential oil from four tropical medicinal plants.
The chemical inhibition of acetyl-cholinesterase (AChE) is a potent strategy for addressing signal related neuropathology and natural products are potential sources of compounds with such properties. Essential oil extracts from leaf, seed, stem and rhizome of four medicinal plants [Aframomum melegueta K. Schum, Crassocephalum crepidioides (Benth S. More), Monodora myristica (Gaertn.), and Ocimum gratissimum (Linn)] were tested for acetyl-cholinesterase inhibitory activity (AChEI) using Ellman's colorimentric method and compared to a reference acetyl-cholinesterase inhibitor (galantamine). The seed (IC50 = 6.71 mg/l) and leaf (IC50 = 6.54 mg/l) extracts from O. gratissimum showed values that matched the capacity of the reference inhibitor (IC50 = 6.62 mg/l). The least potent extract was rhizome extracts of A. melegueta (IC50 = 28.97 mg/l) about four times that of the reference inhibitor. Principal component analysis (PCA) showed that the intrinsic properties (bioactive ingredient factor) of each extract (PC1 = 29.50%) was the most important factor defining the difference or similarity in potency to the reference acetyl-cholinesterase inhibitor while 'dose response' (PC2 = 11.38%) was the second most important factor. The outstanding AChEI property of O. gratissimum extracts could largely be attributed to the high monoterpene content while the weak potency of rhizome extracts of A. melegueta may be attributed to its predominant concentrations of sesquiterpenes. Since potency could be related to interaction between bioactive components, understanding the interaction between ratios of monoterpene and sesquiterpene in extracts could be important in determining their potency for AChEI.


Mechanisms of primary and acquired resistance to immune checkpoint inhibitors in advanced non-small cell lung cancer: A multiplex immunohistochemistry-based single-cell analysis.
Immune checkpoint inhibitors (ICIs) have become a key therapeutic modality for advanced non-small cell lung cancer (NSCLC), but most patients experience primary or acquired resistance to these drugs. We here explored the mechanisms underlying both types of ICI resistance by analysis of the tumor immune microenvironment (TME). Four patients who experienced a long-term response to ICI treatment (progression-free survival [PFS] of ≥12 months) followed by disease progression, after which a rebiopsy was immediately performed (cohort-A), as well as four patients who experienced early tumor progression during ICI treatment (PFS of <9 weeks, cohort-B) were enrolled in this retrospective study. The pretreatment TME was evaluated by 16- or 17-color multiplex immunohistochemistry (mIHC)-based spatial profiling at the single-cell level for both cohorts. In cohort-A, changes in the TME after disease progression during ICI treatment were also investigated by mIHC analysis and transcriptomic analysis. Pretreatment tumor tissue from cohort-B manifested poor infiltration of tumor-reactive CD8+ T cells characterized by CD39 and CD103 expression or by programmed cell death-1 expression, implicating insufficient recognition of tumor cells by CD8+ T cells as a mechanism of primary ICI resistance. Analysis of the paired tumor specimens from cohort-A revealed various changes in the TME associated with acquired ICI resistance, including substantial infiltration of myeloid-derived suppressor cells and M2-type tumor-associated macrophages without a marked decline in the number of tumor-reactive CD8+ T cells; a decrease in the number of tumor-reactive CD8+ T cells; and an apparent decrease in neoantigen presentation by tumor cells. The presence of intratumoral tumor-reactive CD8+ T cells may be a prerequisite for a long-term response to ICI treatment in advanced NSCLC, but it is not sufficient for cancer cell eradication. Various TME profiles are associated with acquired ICI resistance, suggesting that patient-specific strategies to overcome such resistance may be necessary.


Synthesis, cellular localization, and quantification of penton-dodecahedron in serotype 3 adenovirus-infected cells.
Adenovirus penton is a non-covalent complex composed of the penton base and fiber proteins, localized at the twelve vertices of the icosahedral virus capsid. In cells infected by adenovirus serotype 3 (Ad3), penton is found not only in the virus capsid but also self-assembled in dodecahedra formed through interactions between the twelve penton bases. In this study, the intracellular trafficking of penton proteins from the cytoplasm to the nucleus has been followed, and the nuclear re-arrangement induced by viral infection has been observed by electron microscopy of ultrathin sections. The amount of dodecahedra has been assessed in relation to the number of Ad3 infectious virions produced during the Ad3 replication cycle. It appears that dodecahedra are produced in a large excess over viral infectious particles and that they are located intranuclearly along the nuclear membrane of Ad3-infected cells at late times of infection.


Effects of high doses of enalapril and benazepril on the pharmacologically activated renin-angiotensin-aldosterone system in clinically normal dogs.
To determine whether high doses of enalapril and benazepril would be more effective than standard doses of these drugs in suppressing the furosemide-activated renin-angiotensin-aldosterone system (RAAS). 6 healthy Beagles. 2 experiments were conducted; each lasted 10 days, separated by a 2-week washout period. In experiment 1, all dogs received furosemide (2 mg/kg, PO, q 12 h) and enalapril (1 mg/kg, PO, q 12 h) for 8 days (days 0 through 7). In experiment 2, dogs received furosemide (2 mg/kg, PO, q 12 h) and benazepril (1 mg/kg, PO, q 12 h) for 8 days. Effects on the RAAS were determined by assessing serum angiotensin-converting enzyme (ACE) activity on days -1, 3, and 7; serum aldosterone concentration on days -2, -1, 1, 3, and 7; and the urinary aldosterone-creatinine ratio (UAldo:C) in urine collected in the morning and evening of days -2, -1, 1, 3, and 7. High doses of enalapril and benazepril caused significant reductions in serum ACE activity on all days but were not more effective than standard doses used in other studies. Mean UAldo:C remained significantly higher on days 2 through 7, compared with baseline values. Serum aldosterone concentration also increased after drug administration, which mirrored changes in the UAldo:C. In this study, administration of high doses of enalapril and benazepril significantly inhibited ACE activity, yet did not prevent increases in mean urine and serum aldosterone concentrations resulting from furosemide activation of RAAS. This suggested that aldosterone breakthrough from ACE inhibition was a dose-independent effect of ACE inhibitors.


Benefits, complications, and care of implantable infusion devices in 31 children with cancer.
This retrospective study of 31 pediatric oncology patients with subcutaneously implanted infusion devices details the required care and demonstrates the benefits and complications of the system. The Port-a-cath device was used in 29 patients; one had an Infuse-a-port, and two had Mediports. Ages of the patients ranged from 5 months to 16 years. The average time of catheter function was more than 163 +/- 149 days and the total experience was 5,208 patient catheter days. In all, five catheters were removed, one for suspected and one for proven infection, two with extravasations, and one patient had spontaneous extrusion and thrombosis. These totally implanted devices allowed safe administration of blood products, antibiotics, short-term hyperalimentation, and sclerosing chemotherapeutic agents to pediatric oncology patients with previously compromised venous access.


Predation and the evolution of complex oviposition behaviour in Amazon rainforest frogs.
Terrestrial oviposition with free-living aquatic larvae is a common reproductive mode used by amphibians within the central Amazonian rainforest. We investigated the factors presently associated with diversity of microhabitats (waterbodies) that may be maintaining the diversity of reproductive modes. In particular, desiccation, predation by fish, competition with other anurans and water quality were examined in 11 waterbodies as possible forces leading to the evolution of terrestrial oviposition. Predation experiments demonstrated that fish generally do not eat anuran eggs, and that predacious tadpoles and dytiscid beetle larvae are voracious predators of anuran eggs. The percentage of species with terrestrial oviposition was only weakly correlated with the occurrence of pond drying, pH and oxygen concentration, suggesting that anurans in this tropical community are able to use the range of water quality available for egg development. There was a tendency for terrestrial oviposition to be associated with the number of species of tadpoles using the waterbody, but we consider this to be spurious as there was no obvious competitive mechanism that could result in this relationship. The percentage of species with terrestrial oviposition was significantly positively related to our index of egg predation pressure, and negatively related to our index of fish biomass. Egg predation pressure was also negatively related to the index of fish biomass. These results allow us to discount as improbable the hypothesis that predation by fish on anuran eggs was an important selective pressure leading to terrestrial oviposition in this community. The strong positive relationship between terrestrial oviposition and our index of egg predation pressure indicates that these predators have exerted, and are exerting, a significant selective pressure for terrestrial oviposition. The strong negative relationship between the occurrence of fish and the egg predators suggests the surprising conclusion that the presence of fish actually protects aquatic anuran eggs from predation in this tropical system, and allows aquatic oviposition to dominate only in those waterbodies with moderate to high densities of fish. Our results suggest that terrestrial oviposition is a "fixed predator avoidance" trait.


Rheb regulates mitophagy induced by mitochondrial energetic status.
Mitophagy has been recently described as a mechanism of elimination of damaged organelles. Although the regulation of the amount of mitochondria is a core issue concerning cellular energy homeostasis, the relationship between mitochondrial degradation and energetic activity has not yet been considered. Here, we report that the stimulation of mitochondrial oxidative phosphorylation enhances mitochondrial renewal by increasing its degradation rate. Upon high oxidative phosphorylation activity, we found that the small GTPase Rheb is recruited to the mitochondrial outer membrane. This mitochondrial localization of Rheb promotes mitophagy through a physical interaction with the mitochondrial autophagic receptor Nix and the autophagosomal protein LC3-II. Thus, Rheb-dependent mitophagy contributes to the maintenance of optimal mitochondrial energy production. Our data suggest that mitochondrial degradation contributes to a bulk renewal of the organelle in order to prevent mitochondrial aging and to maintain the efficiency of oxidative phosphorylation.


Health-promoting work schedules among nurses and nurse assistants in France: results from nationwide AMADEUS survey.
The study aimed to investigate the relationship between different work schedules and self-reported working conditions and health risk behaviours among nurses and nurse assistants (NNA) in France. It hypothesized that work schedules, particularly long shifts, could impact work-life balance, workload, stress levels, burnout, and smoking habits. NNA had the option to work either with a 7-hour schedule, 5 days per week, or with long work schedules consisting of ten to twelve-hour shifts, three days per week. These schedules could potentially influence various aspects of their professional lives. The survey followed the guidelines of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and was administered to NNA working in public and private national healthcare facilities in France. The researchers used the Job Content Questionnaire to assess the work environment and the French version of the 22-item Maslach Burnout Inventory (MBI) scale to measure burnout. A total of 3,133 NNA participated in the study, including 2,369 nurses (75.6%) and 764 nurse assistants (24.4%). Among them, 1,811 individuals (57.8%) followed a 7-hour work schedule, while 1,322 individuals (42.2%) had a long work schedule. Multivariate analyses revealed that NNA working with long schedules reported higher psychological demands, more frequent burnout, a higher number of daily smoked cigarettes, and greater coffee consumption. These findings were independent of other factors such as sector of employment, type of healthcare facility, job status, work schedules, night shifts, department specialty, age, and family responsibilities. While some NNA may choose long schedules to have more days off, those working with these schedules experience greater work-related burdens and engage in worse health risk behaviours as a coping mechanism. It emphasizes the importance of considering health-promoting work schedules to address the high psychological demands and burnout experienced by NNA with long schedules. Implementing changes in work schedules could potentially improve the overall well-being and job satisfaction of these healthcare professionals.