[Patent protection in modern medical technology].
Inventions related to medical treatments and devices are due to specific regulations in the German, European and US patent Law much more difficult to obtain than inventions in the field of ordinary mechanics. In particular, inventions related to treatments of the human or animal body are excluded from patentability. In order to obtain at least some patent protection for such inventions the wording of the claims as well as the wording of the specification and preferred embodiments is very important. Patent protection is in most cases the only remedy to return the investment spent for the research. To maximize the possibility of patent protection in many countries, the timing of publication of the research result and filing of the patent application must be coordinated.


Imaging of pulmonary venous developmental anomalies.
The purpose of this article is to review pulmonary venous embryology and to present the imaging findings of a variety of pulmonary venous developmental anomalies, including total anomalous pulmonary venous connection, partial anomalous pulmonary venous connection, pulmonary vein stenosis and hypoplasia/atresia, and cor triatriatum. There are numerous developmental pulmonary venous anomalies. Although these conditions have traditionally been evaluated with echocardiography and angiography, they can be accurately diagnosed using both MRI and MDCT.


The use of hypnosis in the treatment of psychogenic oral pain.
Psychogenic pain has been described in many parts of the body such as limbs, digestive system, respiratory organs, and obstetrics. Computer searches have not found a single published case of psychogenic pain of dental origin. Two such cases are described within this paper, which describes pain severe enough to interfere with normal daily activity. The first describes a situation which resulted in 5 operations being performed before an adequate diagnosis was made and treatment started with hypnosis. The second was an inability to work, sleep, and lead a normal existence because of pain which had no organic origin. Hypnosis treatment allowed the patient to have a proper diagnosis before any operative treatment was given and resume normal activity.


Single crystal X-ray structure of tetrahedral C60F36: the most aromatic and distorted fullerene.
Tetrahedral C60F36 is shown by its single-crystal X-ray structure to be the most aromatic (and distorted) fullerene derivative, having four planar hexagons with almost equal bond lengths, the average of which (1.373 A) is the same as in C60F18; one exceptionally long FC-CF bond (1.665 A) corresponds to the similarly long bond in C60F18 (a motif of T C60F36) and is likely to be the site of oxygen insertion in C60F36O.


Reactive oxygen species generation in gingival fibroblasts of Down syndrome patients detected by electron spin resonance spectroscopy.
Oral manifestations of Down syndrome include high susceptibility to gingival inflammation with early onset and rapidly progressive periodontitis. The influence of reactive oxygen species (ROS) on periodontitis of Down syndrome is unclear. The aim of this study was to characterize ROS formation in Down syndrome-gingival fibroblasts (DS-GF) using electron spin resonance (ESR) spin trapping with 5,5-dimetyl-1-pyrolline-N-oxide (DMPO), and to determine whether ROS generation plays a role in the pathogenesis of periodontitis in Down syndrome patients. We observed formation of the DMPO-OH spin adduct, indicating HO* generation from cultured DS-GF and non-DS-GF. The increased HO* generation in cultured DS-GF was strongly decreased in the presence of the H2O2 scavenger, catalase, or the iron chelator, desferal. This may due to the enzymatic ability of over-expressed CuZn-superoxide dismutase in Down syndrome to catalyze the formation of H2O2 from O2*-, thereby increasing the availability of substrate H2O2 for the iron-dependent generation of HO* via the Fenton reaction, suggesting that HO* generated from DS-GF may be involved in progressive periodontitis of Down syndrome.


Temporal Volume Change of Cavernous Sinus Cavernous Hemangiomas after Gamma Knife Surgery.
Cavernous hemangiomas occur very rarely in the cavernous sinus. This study aimed to evaluate the efficacy of Gamma Knife surgery (GKS) on cavernous sinus cavernous hemangioma (CSCH) and to analyze the temporal volume change. We retrospectively reviewed the clinical data of 26 CSCH patients who were treated with GKS between 2001 and 2017. Before GKS, 11 patients (42.3%) had cranial neuropathies and 5 patients (19.2%) complained of headache, whereas 10 patients (38.5%) were initially asymptomatic. The mean pre-GKS mass volume was 9.3 mL (range, 0.5-31.6 mL), and the margin dose ranged from 13 to 15 Gy according to the mass volume and the proximity to the optic pathway. All cranial neuropathy patients and half of headache patients showed clinical improvement. All 26 patients achieved mass control; remarkable responses (less than 1/3 of the initial mass volume) were shown in 19 patients (73.1%) and moderate responses (more than 1/3 and less than 2/3) in 7 patients (26.9%). The mean final mass volume after GKS was 1.8 mL (range, 0-12.6 mL). The mean mass volume at 6 months after GKS was 45% (range, 5-80%) compared to the mass volume before GKS and 21% (range, 0-70%) at 12 months. The higher radiation dose tended to induce more rapid and greater volume reduction. No treatment-related complication was observed during the follow-up period. GKS could be an effective and safe therapeutic strategy for CSCH. GKS induced very rapid volume reduction compared to other benign brain tumors.


Phosphatidic Acid synthesis in castor bean endosperm.
Enzyme assays on organelles isolated from the endosperm of castor bean (Ricinus communis var. Hale) by sucrose density gradient centrifugation showed that palmitoyl-CoA:sn-glycerol 3-phosphate acyltransferase (EC 18.104.22.168) was localized in the membranes of the endoplasmic reticulum. Mn(2+) was required for activity, but Ca(2+) and Mg(2+) could substitute for Mn(2+) at higher concentrations. The apparent Km was 170 mum for sn-glycerol 3-phosphate and approximately 8 mum for palmitoyl-CoA. The optimum pH range was 7 to 7.5 and the principal reaction product was diacyl-sn-glycerol 3-phosphate (phosphatidic acid). Monoacyl-sn-glycerol 3-phosphate (lysophosphatidic acid) was not released as a free intermediate in the reaction. The maximum activity of the enzyme occurred immediately after imbibition, preceding the development of mitochondria and glyoxysomes.


Protective influence of spayed and androgen-treated females on oestrous cycle in food-restricted mice.
Diet restriction induced disruption of oestrous cycle in regularly cycling female mice. The irregularities in the oestrous cycle in females were directly related to the degree of diet restriction. The presence of spayed and androgen-treated females prevented these irregularities and helped to maintain regular oestrous cycles in underfed females. The ability of androgen-treated females to prevent the irregularities in the oestrous cycle in underfed females was inversely related to the degree of diet restriction. The results suggest that the production of the male-originating pheromone that helps to prevent the underfeeding-induced disruption of oestrous cycles in females is androgen-dependent.


Cryptococcal cellulitis in a patient on prednisone monotherapy for myasthenia gravis.
The development of cutaneous cryptococcosis is extremely rare in the human immunodeficiency virus-negative population. The cutaneous manifestations vary greatly, with the rarest presenting as cellulitis. We report a unique case of a 64-year-old woman who had been on prednisone monotherapy for the treatment of myasthenia gravis and subsequently developed cryptococcal cellulitis. This case provides an opportunity to discuss the importance of including cryptococcal cellulitis in the differential diagnosis of cellulitis in a patient on low-dose prednisone who is not responding to empiric antibiotic therapy. Early recognition is crucial as cutaneous manifestations are usually the first sign of disseminated cryptococcosis.


Cadherin-6 is a putative tumor suppressor and target of epigenetically dysregulated miR-429 in cholangiocarcinoma.
Cholangiocarcinoma (CC) is a rare malignancy of the extrahepatic or intrahepatic biliary tract with an outstanding poor prognosis. Non-surgical therapeutic regimens result in minimally improved survival of CC patients. Global genomic analyses identified a few recurrently mutated genes, some of them in genes involved in epigenetic patterning. In a previous study, we demonstrated global DNA methylation changes in CC, indicating major contribution of epigenetic alterations to cholangiocarcinogenesis. Here, we aimed at the identification and characterization of CC-related, differentially methylated regions (DMRs) in potential microRNA promoters and of genes targeted by identified microRNAs. Twenty-seven hypermethylated and 13 hypomethylated potential promoter regions of microRNAs, known to be associated with cancer-related pathways like Wnt, ErbB, and PI3K-Akt signaling, were identified. Selected DMRs were confirmed in 2 independent patient cohorts. Inverse correlation between promoter methylation and expression suggested miR-129-2 and members of the miR-200 family (miR-200a, miR-200b, and miR-429) as novel tumor suppressors and oncomiRs, respectively, in CC. Tumor suppressor genes deleted in liver cancer 1 (DLC1), F-box/WD-repeat-containing protein 7 (FBXW7), and cadherin-6 (CDH6) were identified as presumed targets in CC. Tissue microarrays of a representative and well-characterized cohort of biliary tract cancers (n=212) displayed stepwise downregulation of CDH6 and association with poor patient outcome. Ectopic expression of CDH6 on the other hand, delayed growth in the CC cell lines EGI-1 and TFK-1, together suggesting a tumor suppressive function of CDH6. Our work represents a valuable repository for the study of epigenetically altered miRNAs in cholangiocarcinogenesis and novel putative, CC-related tumor suppressive miRNAs and oncomiRs.


Risk and burden associated with the acquisition of viral hepatitis A and B in the corporate traveler.
As the number of international business travelers continues to grow, so does the list of destinations, many of which are endemic for both hepatitis A and B. Generally, travelers are unaware of the risks of acquiring viral hepatitis when traveling; many are unsure of modes of transmission and do not seek pretravel advice or do not follow the recommendations of travel health professionals. Infected employees can result in increased health care costs and reduced productivity in the workplace. Safe and efficacious monovalent vaccines and a combined hepatitis A and B vaccine are available. Successful corporate health and immunization programs can prevent hepatitis A and B when employees are abroad on business. This article examines the distribution, risks, costs, burden, and prevention of hepatitis A and B in the international business traveler.


Microendemicity in the northern Hajar Mountains of Oman and the United Arab Emirates with the description of two new species of geckos of the genus Asaccus (Squamata: Phyllodactylidae).
The Hajar Mountains of Oman and the United Arab Emirates (UAE) is the highest mountain range in Eastern Arabia. As a result of their old geological origin, geographical isolation, complex topography and local climate, these mountains provide an important refuge for endemic and relict species of plants and animals with strong Indo-Iranian affinities. Among vertebrates, the rock climbing nocturnal geckos of the genus Asaccus represent the genus with the highest number of endemic species in the Hajar Mountains. Recent taxonomic studies on the Zagros populations of Asaccus have shown that this genus is much richer than it was previously thought and preliminary morphological and molecular data suggest that its diversity in Arabia may also be underestimated. A total of 83 specimens originally classified as Asaccus caudivolvulus (including specimens of the two new species described herein), six other Asaccus species from the Hajar and the Zagros Mountains and two representatives of the genus Haemodracon were sequenced for up to 2,311 base pairs including the mitochondrial 12S and cytb and the nuclear c-mos, MC1R and ACM4 genes. Phylogenetic relationships were inferred using both Bayesian and maximum-likelihood approaches and the former method was also used to calibrate the phylogenetic tree. Haplotype networks and phylogenetic trees were inferred from the phased nuclear genes only. Sixty-one alcohol-preserved adult specimens originally classified as Asaccus caudivolvulus from the northern Hajar Mountains were examined for 13 morphometric and the five meristic variables using multivariate methods and were also used to diagnose and describe the two new species. The results of the molecular and morphological analyses indicate that the species originally classified as Asaccus caudivolvulus is, in fact, an assemblage of three different species that started diversifying during the Mid-Miocene. The molecular phylogenies consistently recovered the Hajar endemic A. montanus as sister taxon to all the other Asaccus species included in the analyses, rendering the Arabian species of Asaccus polyphyletic. Using this integrative approach we have uncovered a very old diversification event that has resulted in a case of microendemicity, where three morphologically and ecologically similar medium-sized lizard species coexist in a very short and narrow mountain stretch. Asaccus caudivolvulus is restricted to a small coastal area of the UAE and at risk from heavy development, while the two new species described herein are widely distributed across the northern tip of the Hajar Mountains and seem to segregate in altitude when found in close proximity in the Musandam Peninsula (Oman). Similarly to other integrative analyses of Hajar reptiles, this study highlights the high level of diversity and endemicity of this arid mountain range, underscoring its status as one of the top hotspots of reptile diversity in Arabia.


Continuing therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of methotrexate, 6-mercaptopurine and 6-thioguanine.
Across the world, therapy with 6-mercaptopurine (6-MP) and methotrexate (MTX) forms the basis of the continuing therapy of childhood acute lymphoblastic leukaemia (ALL). In this review, the pharmacological determinants of the sensitivity of human leukaemia cell lines and lymphoblasts derived from children with ALL will be discussed. In addition, clinical pharmacological studies of 6-MP and MTX in relation to the continuing therapy with childhood ALL will be reviewed. For 6-MP in vitro, prolonged exposure times to relatively high extracellular drug concentrations are necessary for cytotoxicity, and these concentrations are much higher than those achieved during continuing therapy for childhood ALL. For MTX, plasma concentrations are achieved during continuing therapy that would be cytotoxic to human leukaemia cells during prolonged exposures in vitro. For both MTX and 6-MP, wide inter- and intrapatient variation in plasma pharmacokinetic parameters has been described. For 6-MP and MTX, cellular pharmacological studies have been largely restricted to erythrocytes as a surrogate of the possible effects in leukaemic blasts. Although measures of the pharmacology of 6-MP and MTX in erythrocytes has been related to prognosis in many studies, 6-MP systemic exposure and the dose intensity of 6-MP and MTX actually received by children during this phase of therapy seems to be the most important determinant of efficacy. Further studies will be needed to determine the importance of pharmacokinetic variability during continuing therapy as a determinant of outcome for children with ALL. In this respect, minimal residual disease status during this phase of treatment may prove to be a useful pharmacodynamic endpoint.


COX 2-selective NSAIDs: biology, promises, and concerns.
Celecoxib (Celebrex) is the first of a new family of nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit cyclooxygenase 2 (COX 2) while sparing COX 1. Clinical trials indicate that it is approximately as effective in relieving the pain of osteoarthritis and the pain and inflammation of rheumatoid arthritis as nonselective NSAIDs, but causes less gastrointestinal ulceration and bleeding. This paper reviews the pharmacology and possible clinical role of celecoxib and other COX 2-selective NSAIDs.


[Rpn4p is a positive and negative transcriptional regulator of the ubiquitin-proteasome system].
Ubiquitin-proteasome proteolytic system participates in metabolism of the majority of intracellular proteins and regulation of key cellular processes in eukaryotes. While the structure and functioning of this system is studied rather well, a little is known about regulation of its genes expression. At present time, the only regulatory system of transcription of proteasome genes is found in the yeast Saccharomyces cerevisiae. This system includes Rpn4p-proteasome-associated transcriptional regulator and its binding site called PACE (Proteasome Associated Control Element). To learn more about function of Rpn4p as a transcriptional regulator, there are following questions: 1) is the Rpn4p regulator for PACE-containing genes which encode for components of protein ubiquitinylation system 2) what is the contribution of Rpn4p in stress-activated level of mRNA of proteasome genes. In this work, using semiquantitative RT-PCR we have shown that deletion of RPN4 gene leads to decreasing in mRNA level of the genes of ubiqitination system RAD6, RAD23 and CDC48, while UBI4 mRNA level is increased in this strain. In the presence of alkylating agent methyl methanesulfonate or under heat shock we observed Rpn4 p-dependent elevation of mRNA level of the proteasomal genes RPT4 and RPNS. At the same time, CDC48 mRNA level is decreased in wild type yeast strain upon methyl methanesulfonate treatment. These data indicate that under normal or stress conditions Rpn4p may act as an activator or repressor for the genes of the ubiquitin-proteasome system.


Asymmetric Mannich reactions of imidazo[2,1-b]thiazole-derived nucleophiles with (S(S))-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine.
Asymmetric Mannich reactions of imidazo[2,1-b]thiazole-derived nucleophiles with (SS)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine were found to proceed with reasonably good yields (55%-79%) and exceptionally high stereoselectivity (>99 : 1 dr). This method presents a general approach for the preparation of a new type of biologically relevant compounds containing pharmacophoric imidazo[2,1-b]thiazole and (trifluoro)ethylamine groups.


Paracervical block anesthesia in labour.
The efficacy and safety of paracervical block anesthesia were studied in 153 patients in the first stage of labour. Transient decrease in uterine activity was noted in 77 patients. There was no acceleration in cervical dilatation following the block. The duration of action of the block in 80 primiparas was 31 to 120 minutes in 69, and over 120 minutes in five. In the 73 multiparas, 53 of the blocks lasted 31 to 90 minutes, eight from 90 to 120 minutes, and two over 120 minutes. The results were good in 66 primiparas and 54 multiparas. The blocks failed in four primiparas and six multiparas. Twenty-six infants had low Apgar scores, but in none could this be related to the paracervical block. There were no significant fetal or maternal complications.


[SOME ASPECTS OF THE IMPACT OF THE COVID-19 PANDEMIC ON THE MENTAL STATE OF PEOPLE WITH THE HUMAN IMMUNODEFICIENCY VIRUS].
The purpose of this article is to study individual aspects of the impact of the COVID-19 pandemic on the mental state of PLHIV. The study covered 146 patients with HIV-related diseases who attended the outpatient department of the communal enterprise "Dnepropetrovsk Regional Center for Socially Significant Diseases of the Dnepropetrovsk Regional Council" during September-October 2020. HIV-infected were interviewed using a self-developed questionnaire. We used integrative test of anxiety by A.P. Bizyuk to investigate anxiety. The frequency of increased anxiety over the past half year among respondents is 15.75%; frequency of insomnia, weight loss, eating disorders - 12.32%; In 10.42% (n=15) cases, PLHIV had episodes of acute feelings of fear, palpitations, shortness of breath, chest tightness, panic while watching news about COVID-19. A high level of average value of situational anxiety among PLHIV was revealed - 7.8 (1.3) stanins - M (SD), in the structure of which "social defense reactions", a phobic component and anxious assessment of prospects prevail. 74.6% of HIV-infected strictly adhered to additional protection against COVID-19; 63.01% - considered crowded places a threat to their health; 52.74% were afraid to get sick with COVID-19; 49.31% - had an increased interest of PLHIV in COVID-19 in Ukraine and the world. The respondents used the following additional methods of protection: self-isolation (60%), strict adherence to distance (75%), disinfection of their belongings and household items (10%). The mental state of PLHIV during the coronavirus pandemic indicates the presence of symptoms of distress: the manifestations of anxiety-depressive disorders, insomnia have increased, a fixation has appeared on their physical condition, social isolation and distancing have increased. Further research into the characteristics of the psychoemotional state of PLHIV will help improve the organization of medical and social assistance in the current situation of the COVID-19 pandemic.


Neurally mediated syncope: pathophysiology and implications for treatment.
Neurally mediated syncope may occur in patients whose hemodynamic picture does not fit the characteristics of orthostatic intolerance as described elsewhere in this issue. Nonetheless, patients who suffer from neurocardiogenic or vasovagal syncope may be seriously incapacitated by their episodes of syncope or presyncope. Although it has been assumed that vagal activation as a result of stimulation of ventricular mechanoreceptors is essential to the production of these episodes, several critical observations are presented that suggest that other mechanisms may also be operative in some patient subsets. In addition, evidence is presented that the sympathetic responses of many of these patients may be reduced rather than increased and that abnormal baroreflex responsiveness may also play an causative role. These findings suggest new avenues for therapy in this field in which carefully controlled, randomized, double-blind trials are scarce.


Whole eye wavefront aberrations in Mexican male subjects.
To analyze the characteristics, incidence, and appearance of wavefront aberrations in undilated, normal, unoperated eyes. Eighty-eight eyes of 44 healthy male Mexican subjects (mean age 25.32 years, range 18 to 36 yr) were divided into three groups based on uncorrected visual acuity of greater than or equal to 20/20, 20/30, or 20/40. UCVA measurements were obtained using an Acuity Max computer screen chart. Wavefront aberrations were measured with the Nidek OPD-Scan ARK 10000, Ver. 1.11b. All measurements were carried out at the same center by the same technician during a single session, following manufacturer instructions. Background illumination was 3 Lux. Wavefront aberration measurements for each group were statistically analyzed using StatView; an average eye was characterized and the resulting aberrations were simulated using MATLAB. We obtained wavefront aberration maps for the 20/20 undilated normal unoperated eyes for total, low, and high order aberration coefficients. Wavefront maps for right eyes were practically the same as those for left eyes. Higher aberrations did not contribute substantially to total wavefront analysis. Average aberrations of this "normal eye" will be used as criteria to decide the necessity of wavefront-guided ablation in our facilities. We will focus on the nearly zero average of high order aberrations in this normal whole eye as a reference to be matched.


GB virus C/hepatitis G virus in serum and liver of patients with chronic C and non B non C hepatitis: molecular and immunological aspects.
GB virus C/hepatitis G Virus (HGV) is a single-stranded RNA virus that is transmitted parenteraly. This study investigates GB virus C in 62 patients with chronic hepatitis C (CHC) and non B non C hepatitis (CNBNC). The viral E2 protein was examined in the sera of the patients (using western blott assay) while viral replication in the liver was examined by detecting the negative strand of HGV-RNA and its E2 protein in liver tissue using in situ hybridization and immunohistochemical staining respectively. E2 protein was detected in 28% of patients with chronic hepatitis C and in 13.3% of patients with non B non C chronic hepatitis, while not detected in healthy blood donors (0%). HGV- E2 protein and the negative strand of HGV -RNA were detected in hepatocytes of only 3 out of the 13 examined liver biopsies from HGV infected patients (23%). The mean level of ALT in chronic HCV hepatitis patients who were +ve for HGV was significantly lower than those who were -ve for HGV. There was a significant difference between the mean value of HCV -RNA level by real time PCR in sera of hepatitis C positive patients with + ve HGV-E2 when compared with HCV patients with - ve HGV-E2 (p < 0.001). It is concluded that HGV co-infection may occur in some cases with CHC and CNBNC. Sites of replication, other than liver, are suggested as the virus was detected in liver tissue of only 23 % of cases inspite of its presence in their sera.


The generation of oxidation products of benzo[a]pyrene by lipid peroxidation: a study using gamma-irradiation.
The role which active oxygen and radicals generated by the peroxidation of unsaturated fatty acids could play in the oxidation of benzo[a]pyrene has been studied using gamma-irradiation. Irradiation of benzo[a]pyrene resulted in the formation of benzo[a]pyrene 1,6-, 3,6- and 6,12-quinones and other more polar products which were analysed by h.p.l.c. OH. radicals are believed to be involved in this oxidation. The presence of polyunsaturated fatty acids and polyunsaturated lipids stimulated the formation of benzo[a]pyrene products following gamma-irradiation. Oxidation of benzo[a]pyrene also occurred over a period of days in the presence of autoxidising mackerel oil. The rate of benzo[a]pyrene oxidation was related to the extent of lipid peroxidation as determined by malonaldehyde formation. Malonaldehyde production as a result of peroxidising lipids was inhibited by benzo[a]pyrene which suggested that benzo[a]pyrene reacted directly with lipid peroxy radicals or hydroperoxides generated in the process of lipid peroxidation. These results demonstrate that oxidation products of the peroxidation of lipids and fatty acids are able to react directly with benzo[a]pyrene to form products including benzo[a]pyrene quinones without the presence of enzymes such as the cytochrome P-450 mixed function oxidase system and prostaglandin synthetase. It is possible that benzo[a]pyrene may be activated by these types of reactions in vivo or in vitro when benzo[a]pyrene is in contact with polyunsaturated lipids in foodstuffs or the intestinal lumen and peroxidation of unsaturated fats may play an important role in human carcinogenesis.


Ventilatory response to sustained hypoxia during exercise.
The ventilatory stimulating effects of hypoxia occurring at carotid bodies are potentiated by exercise. However, hypoxia also has central ventilatory depressive effects; the potential interactions between this hypoxic depression and exercise have not been studied. We examined the ventilatory response to a 20 min period of isocapnic hypoxia (end-tidal O2, PETO2, of 50 mm Hg), preceded and followed by a 5 min period of isocapnic hyperoxia in seven normal adult males at rest and during moderate exercise (45-75 W). When hypoxia was introduced at rest (PETO2 = 42 mmHg), ventilation initially increased from 13.73 +/- 3.04 (mean +/- SD) to 23.69 +/- 5.48 1.min-1 and then slowly declined to 19.01 +/- 4.68 1 min-1. The increase was caused by increases in tidal volume and respiratory frequency, but the decline was solely in tidal volume. During a background of moderate exercise (PETCO2 = 46 mmHg), introduction of hypoxia caused ventilation to increase from 30.84 +/- 6.31 to 56.44 +/- 10.58 1.min-1. Ventilation subsequently did not decline; at the end of the hypoxic period, ventilation was 57.06 +/- 12.59 1.min-1. The increase was also associated with an increase in tidal volume and respiratory frequency, as seen as rest, but with much larger magnitudes. Despite the absence of ventilatory decline, there was still a decline in tidal volume, but it was compensated by an increase in respiratory frequency. We conclude that exercise potentiated the acute ventilatory response to hypoxia by modifying both tidal volume and respiratory frequency but that exercise abolished or greatly reduced hypoxic decline by increasing respiratory rate.


Localisation microscopy with quantum dots using non-negative matrix factorisation.
We propose non-negative matrix factorisation with iterative restarts (iNMF) to model a noisy dataset of highly overlapping fluorophores with intermittent intensities. We can recover high-resolution images of individual sources from the optimised model, despite their high mutual overlap in the original data. Each source can have an arbitrary, unknown shape of the PSF and blinking behaviour. This allows us to use quantum dots as bright and stable fluorophores for localisation microscopy. We compare the iNMF results to CSSTORM, 3B and bSOFI. iNMF shows superior performance in the challenging task of super-resolution imaging using quantum dots. We can also retrieve axial localisation of the sources from the shape of the recovered PSF.


[Facial cellulite associated with mandibular osteomyelitis in an infant].
The discovery of a jugular tumefaction in an infant evokes several diseases. We report the case of a 4-month-old infant whose jugular cellulite revealed mandibular osteomyelitis. A 4-month-old boy was referred for hard, hot tumefaction of the right cheek and multiple cervical adenopathies. The suggested diagnosis was cellulite of cutaneous origin. He presented 21 900/mm(3) hyperleukocytosis associated with an inflammatory biological syndrome. Standard x-ray of the facial mass was normal. Sonography of the face showed thickening of the soft subcutaneous tissues and retro and sub-mandibular adenopathies with abcedation. Antibiotherapy with amoxicillin and clavulanic acid led to rapid improvement. Three days after withdrawal of the antibiotherapy, the tumefaction recurred without fever. A facial scan eliminated cystic lymphangioma and showed osteolysis of the external plateau of the ascending branch of the mandible with periosteal appositions. Histological examination of a surgical bone biopsy showed infectious osteitis and culture revealed hemolytic beta streptococci. Six weeks of antibiotherapy (initially with amoxicillin and gentamycin, then amoxicillin in monotherapy) led to the regression of all cutaneous signs. When confronted with a tumefaction in this area, malignant or benign tumoral causes such as cystic lymphangioma must be eliminated. Infectious causes (abscess, parotid inflammation and osteomyelitis) must be evoked and distinguished from infantile cortical hyperostosis (Caffey-Silverman's syndrome). Standard radiological imaging, scan or scintigraphy are useful diagnostic tools. If osteolysis is discovered, a biopsy must be taken for anatomopathological and biological examination.


Development of simple clinical criteria for the definition of inflammatory arthritis, enthesitis, dactylitis, and spondylitis: a report from the GRAPPA 2012 annual meeting.
Dermatologist and primary care clinicians are in an ideal position to identify the emergence of psoriatic arthritis (PsA) in patients with psoriasis. Yet these clinicians are not well trained to distinguish inflammatory musculoskeletal disease from other more common problems such as osteoarthritis, traumatic or degenerative tendonitis and back pain, or fibromyalgia. A simple set of clinical criteria to identify inflammatory disease would aid recognition of PsA. At its 2012 annual meeting, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) discussed development of evidence-based, practical, and reliable definitions of inflammatory arthritis, enthesitis, dactylitis, and spondylitis. This project will be a sequential process of expert clinician nominal-group technique, patient surveys and focus groups, and Delphi exercises to identify core features of inflammatory disease, testing these in a small group of patients with and without inflammatory disease, and finally validating these criteria in larger groups of patients.


[Prognostic value of decreased vasopressin modulation in the late-phase of septic shock patients].
To investigate the prognostic value of decreased vasopressin (VP) modulation in the late-phase of septic shock. A prospective study was conducted. Fifty-five septic shock patients hospitalized in intensive care unit (ICU) of the First Hospital of Hebei Medical University from January 2012 to February 2014 were enrolled. All patients received 3% hypertonic saline solution infusion. Serum concentrations of sodium and VP were measured before and after hypertonic saline solution infusion. Patients with ratio of difference in sodium and VP before and after infusion of 3% hypertonic saline (ΔVP/ΔNa)≤0.5 pg/mmol were defined as non-responders, and who >0.5 pg/mmol were defined as responders. The levels of lactic acid, C-reactive protein (CRP), and vasoactive drug [dopamine (DA) and norepinephrine (NE)] usage between the two groups were compared. The 28-day mortality, live time in the dead, and ICU day in survivors were analyzed between the two groups. The receiver operating characteristic curve (ROC curve) was drawn to assess prognostic value of VP. There were 30 cases (54.5%) in non-responsive group, and 25 (45.5%) in responsive group. There were no significant differences in the age, acute physiology and chronic health evaluation II (APACHEII) score, central venous pressure (CVP), blood pressure, plasma albumin level, sodium level before and after hypertonic saline solution infusion between the two groups. The baseline level of VP in the non-responsive group was markedly lower than that of the responsive group (ng/L: 10.66 ± 1.57 vs. 17.13 ± 5.12, t=6.091, P<0.001). After hypertonic saline solution infusion, the VP level was also significantly decreased compared with that in the responsive group (ng/L: 11.65 ± 1.74 vs. 22.50 ± 5.31, t=9.758, P<0.001). The non-responders showed higher lactic acid (mmol/L: 3.04 ± 0.55 vs. 2.28 ± 0.38, t=-5.881, P<0.001) and CRP (mg/L: 117.9 ± 23.0 vs. 94.9 ± 17.0, t=-4.143, P<0.001), and received larger dosage of vasoactive drugs [DA (μg × kg⁻¹ × min⁻¹): 14.8 ± 3.9 vs. 8.9 ± 1.6, t=-5.725, P<0.001; NE (μg × kg⁻¹ × min⁻¹): 0.96 ± 0.42 vs. 0.40 ± 0.09, t=-5.625, P<0.001] for maintaining blood pressure compared with those in responders. The non-responsive group showed higher 28-day mortality (66.7% vs. 40.0%, χ² =3.911, P=0.048) and longer ICU day (days: 9.9 ± 2.3 vs. 6.7 ± 1.7, t=-4.044, P<0.001), but the live time in the dead showed no difference between non-responsive group and responsive group (days: 5.8 ± 1.9 vs. 6.1 ± 2.3, t=0.384, P=0.704). ROC curve showed that the area under ROC curve (AUC) for ΔVP/ΔNa predicting the outcome was 0.828, and the ΔVP/ΔNa threshold value of 0.5 pg/mmol had the sensitivity of 66.7% and specificity of 64.0% for prediction of the outcome (95% confidence interval: 0.722-0.934). Osmotic pressure-regulated VP secretion was impaired and decreased in the late-phase of septic shock, and made the sense in prognosis.


Nickel-Catalyzed 3,3-Dialkynylation of 2-Aryl Acrylamides: Direct Access to gem-Diethynylethenes via Double Vinylic C-H Bond Activation.
Direct access to gem-diethynylethenes is achieved by a Ni-catalyzed 3,3-dialkynylation of 2-aryl acrylamides with 1-bromotriisopropylsilylacetylene. The preliminary mechanism study reveals that the reaction goes through a sequential double vinylic C-H bond activation with the assistance of an 8-aminoquinolinyl directing group.


Extraneuronal monoamine transporter expression and DNA repair vis-à-vis 2-chloroethyl-3-sarcosinamide-1-nitrosourea cytotoxicity in human tumor cell lines.
We previously found that 2-chloroethyl-3-sarcosin-amide-1-nitrosourea (SarCNU), a new chloroethylnitrosourea analogue presently in phase I clinical trials, is a selective cytotoxin that enters cells via the extraneuronal transporter for monoamine transmitters (EMT). In this study, we assessed whether EMT expression correlates with SarCNU cytotoxicity by determining EMT expression in 23 human tumor cell lines with reverse-transcription PCR. Western blot analysis was used to measure protein levels of the DNA repair genes, O6-methylguanine-DNA methyltransferase (MGMT), and excision repair cross-complementing rodent repair deficiency gene 2 (ERCC2). SarCNU cytotoxicity was determined by the sulforhodamine B colorimetric anti-cancer-drug screening assay and correlated with gene expression. Almost all of the cell lines screened were positive for EMT expression. However, seven cell lines (MGR-1, MGR-2, T98-G, SKI-1, SKNSH, 297, and GBM) expressed low levels of EMT. Although there was no linear correlation between SarCNU cytotoxicity and EMT expression, SarCNU cytotoxicity significantly correlated with ERCC2 protein levels, and MGMT-rich (Mer+) cell lines (MGMT protein level >0.1) were more resistant to SarCNU than MGMT-poor (Mer-) cell lines (MGMT protein level <0.1). Moreover, multiple regression analysis indicated that the best correlation with SarCNU cytotoxicity was attainable with EMT plus MGMT and ERCC2 expression. This study suggests that in human tumor cell lines both EMT and DNA repair factors, specifically, MGMT and ERCC2, are important determinants of SarCNU activity. Because EMT is expressed in a wide variety of human tumors, SarCNU should be a more widely effective alternative chemotherapeutic agent.


Phytochemical Composition, Anti-Inflammatory and ER Stress-Reducing Potential of Sambucus ebulus L. Fruit Extract.
Sambucus ebulus L. (SE) fruits are used for their immunostimulation, hematopoietic and antiviral potential. Recently, we focused on analyzing the mechanism underlying SE fruit aqueous extract's (FAE) immunomodulation and anti-inflammatory activities, with attention to its endoplasmic reticulum (ER) stress-reducing potential. J774A.1 macrophages were treated with SE FAE alone or in conditions of lipopolysaccharides (LPS) stimulation. Using GC-MS and LC-MS/MS, its phytochemical composition was analyzed. To measure transcription and protein levels, we used qPCR and Western blot, respectively. The prevailing phytochemicals in SE FAE were hydroxycinnamic acids, proanthocyanidins and anthocyanins. The content of some amino acids, organic acids, alcohols, fatty acids and esters were newly reported. Extracts exerted an immunostimulation potential by stimulating IL-6, TNFα, Ccl2, COX2 and iNOS transcription, without inducing ER stress. SE FAE suppressed the LPS-induced transcription of inflammation related genes (IL-1β, IL-6, TNFα, Ccl2, Icam-1, Fabp4, COX2, iNOS, Noxo1, IL-1ra, Sirt-1) and reduced the protein levels of iNOS, peIF2α, ATF6α and CHOP. The effects were comparable to that of salicylic acid. SE suppresses LPS-stimulated inflammatory markers on the transcription and translation levels. Targeting ER stress is possibly another mechanism underlying its anti-inflammatory potential. These findings reveal the potential of SE fruits as a beneficial therapeutic of inflammation and ER stress-related pathological conditions.


The cytotoxicity and apoptosis induced by 4-tertiary butylphenol in human melanocytes are independent of tyrosinase activity.
It has been known for several decades that cutaneous depigmentation, i.e., contact/occupational vitiligo, can be caused by some phenolic derivatives that have a similar structure to tyrosine. Among these phenolic depigmenting agents, 4-tertiary butylphenol is the most potent. The cutaneous depigmentation induced by phenolic derivatives results from the loss of functional melanocytes. Tyrosinase is a melanocyte specific copper-containing enzyme that catalyzes the conversion of the amino acid tyrosine, through a complex series of intermediates, to melanin. In this study we tested the hypothesis that the cytotoxicity induced by 4-tertiary butylphenol is mediated by tyrosinase and occurs via an apoptotic process. Melanocyte cultures derived from African-American and Caucasian donors exhibiting a 3-fold difference in tyrosinase activity and 14-fold difference in melanin content demonstrate comparable concentration-dependent sensitivity to 4-tertiary butylphenol. In addition, cultures of dermal fibroblasts and epidermal keratinocytes exhibited similar and reduced sensitivity, respectively, to 4-tertiary butylphenol compared with autologous melanocytes. Two melanoma cell lines, one melanotic and one amelanotic lacking the expression of both tyrosinase protein and activity, when transfected with the tyrosinase cDNA, exhibited no alteration in its sensitivity to 4-tertiary butylphenol. These data suggest that 4-tertiary butylphenol cytotoxicity is not mediated via tyrosinase. Melanocytes treated with 4-tertiary butylphenol, however, did exhibit plasma membrane blebbing, DNA fragmentation, and phosphatidylserine relocalization indicating that 4-tertiary butylphenol induced melanocyte destruction occurs by an apoptotic process.


'Stolen Time'-Delivering Nursing at the Bottom of a Hierarchy: An Ethnographic Study of Barriers and Facilitators for Evidence-Based Nursing for Patients with Community-Acquired Pneumonia.
The research has reported a high prevalence of low-quality and missed care for patients with community-acquired pneumonia (CAP). Optimised nursing treatment and care will benefit CAP patients. The aim of this study was to describe the barriers and facilitators influencing registered nurses' (RNs') adherence to evidence-based guideline (EBG) recommendations for nursing care (NC) for older patients admitted with CAP. Semi-structured focus group interviews (n = 2), field observations (n = 14), and individual follow-up interviews (n = 10) were conducted in three medical units and analysed by a qualitative content analysis. We found a main theme: ''stolen time'-delivering nursing at the bottom of a hierarchy', and three themes: (1) 'under the dominance of stronger paradigms', (2) 'the loss of professional identity', and (3) 'the power of leadership'. These themes, each comprising two to three subthemes, illustrated that RNs' adherence to EBG recommendations was strongly influenced by the individual RN's professionalism and professional identity; contextual barriers, including the interdisciplinary team, organisational structure, culture, and evaluation of the NC; and the nurse manager's leadership skills. This study identified central factors that may help RNs to understand the underlying dynamics in a healthcare setting hindering and facilitating the performance of NC and make them better equipped for changing practices.


[Ectopic thyroid: report of a case].
The development of thyroid tissue can occur in any moment of the migration of the thyroid along the thyroglossal duct from the tongue, resulting in lingual (at tongue base), sublingual (below the tongue), prelaryngeal (in front of the larynx), and substernal (in the mediastinum) ectopy. Thyroglossal duct cyst is the most common type of clinical abnormality related to thyroid ectopy. Surgical removal of such ectopic tissue is justified since some Authors describe thyroid cancer arising from aberrant thyroid tissue. The Authors report a case of thyroid ectopy in a patient who underwent 20 years before a left thyroid resection with isthmectomy; during the operation the surgeon described a hypertrophic pyramidal lobe which was left in situ and the patients did not receive any hormone suppressing therapy.


Noninvasive monitoring of cerebral blood oxygenation in ovine superior sagittal sinus with novel multi-wavelength optoacoustic system.
Noninvasive monitoring of cerebral blood oxygenation with an optoacoustic technique offers advantages over current invasive and noninvasive methods. We report the results of in vivo studies in the sheep superior sagittal sinus (SSS), a large central cerebral vein. We changed blood oxygenation by increasing and decreasing the inspired fraction of oxygen (FiO(2)). Optoacoustic measurements from the SSS were performed at wavelengths of 700, 800, and 1064 nm using an optical parametric oscillator as a source of pulsed near-infrared light. Actual oxygenation of SSS blood was measured with a CO-Oximeter in blood samples drawn from the SSS through a small craniotomy. The amplitude of the optoacoustic signal induced in the SSS blood at lambda = 1064 nm closely followed the changes in blood oxygenation, at lambda = 800 nm was almost constant, and at lambda = 700 nm was changing in the opposite direction, all in accordance with the absorption spectra of oxy- and deoxyhemoglobin. The optoacoustically predicted oxygenation correlated well with actual blood oxygenation in sheep SSS (R(2) = 0.965 to 0.990). The accuracy was excellent, with a mean difference of 4.8% to 9.3% and a standard deviation of 2.8% to 4.2%. To the best of our knowledge, this paper reports for the first time accurate measurements of cerebral venous blood oxygenation validated against the "gold standard" CO-Oximetry method.


Detection of the Hb Quong Sze mutation in a Chinese family by selective amplification of the alpha 2-globin gene and restriction map analysis with Msp I.
The polymerase chain reaction technique combined with restriction map analysis with Msp I and hybridization with synthetic oligonucleotide probes has been used to identify Hb Quong Sze [alpha 125(H8)Leu----Pro] in a Chinese family in Guangxi (Quong Sze), P. R. China. Our data and those described in an earlier publication (1) indicate that the Hb Quong Sze carriers originate from the same province of the People's Republic of China, namely Guangxi.


Osler-Rendu-Weber syndrome: congenital arteriovenous intrapulmonary fistula treated using a percutaneous Amplatzer plug.
Pulmonary arteriovenous fistulas (PAVFs) are rare vascular malformations (PAVMs) of the lung that could lead to severe hypoxiemia due to right-to-left intrapulmonary shunts. They may occur as isolated entities or associated with Osler-Rendu-Weber syndrome or hereditary haemorrhagic telangiectasia (HHT). We report a case of a 70 years old woman with Rendu-Osler-Weber disease and a large arteriovenous malformation involving the left pulmonary artery. We describe the successful transcatheter occlusion of the PAVF using an Amplatzer vascular plug. This work is an attempt to focus the attention on pulmonary arteriovenous malformations and on percutaneous treatment as an alternative to surgery, that consists of a conservative lung resection.


Maxillofacial senior house officer posts: the trainee's perspective.
A questionnaire was sent out to all the maxillofacial senior house officers in the UK. The purpose of this was to evaluate their perceptions on working conditions, supervision, education and career aspirations. A high proportion (73 percent) returned questionnaires, and from the results of this it seems apparent that there are shortcomings in the supervision and education of SHOs. Based on these findings, a mandatory education programme is advocated that should be recorded in a logbook together with all operative procedures.


Infantile spasms: III. Prognostic implications of bitemporal hypometabolism on positron emission tomography.
Positron emission tomography (PET) of brain glucose utilization is highly sensitive in detecting focal cortical abnormalities in patients with infantile spasms even when the computed tomographic (CT) and magnetic resonance imaging (MRI) scans are normal. Of 110 infants with spasms evaluated for potential surgical intervention during an 8-year period, we encountered 18 infants (7 males, 11 females; age range, 10 mo to 5 yr) with a common metabolic pattern on positron emission tomography (PET) consisting of bilateral hypometabolism in the temporal lobes. CT and MRI scans did not reveal any focal abnormalities in the 18 infants. Video-electroencephalographic monitoring indicated either bilateral or multifocal epileptogenicity, or failed to show any epileptic focus, so that none of the 18 infants were considered candidates for resective surgery. These patients were then enrolled in a prospective study aimed at determining long-term outcome in the presence of bilateral temporal PET hypometabolism. Analysis of outcome in 14 of the 18 subjects (follow-up period, 10 mo to 10 yr 5 mo; mean, 3 yr 11 mo +/- 2 yr 4 mo [SD]) revealed the following: (1) all had severe developmental delay and had failed to gain significant milestones; (2) language development had been minimal or absent; (3) 10 of the 14 met the DSM-IV criteria for autistic disorder. Our findings indicate that patients with infantile spasms and bitemporal glucose hypometabolism on PET comprise a relatively homogeneous group and are typically not candidates for cortical resection. The long-term outcome of these infants is particularly poor and the majority are autistic.


Energy metabolism in mouse pancreas in response to different dosages of a CCK analogue.
Stimulation of the exocrine pancreas with cholecystokinin analogues leads to a variety of intraacinar processes, many coupled to energy consumption. It was hypothesized that extensive ATP depletion could play a role in the pathophysiology of acute pancreatitis, especially in the hyperstimulation (cerulein) model. Mice received seven intraperitoneal injections of cerulein at hourly intervals, at doses ranging from physiological (0.1 micrograms/kg) to pharmacological (50 micrograms/kg). A single dose of cerulein induced a 28-33% decrease in ATP, whereas a complete course of injections led to a nadir as low as 45% of the control value. The overall pattern of ATP tissue content during the observed time course was surprisingly similar in all four groups and statistically not different at any time point. Until 12 h, ATP levels in all groups remained below the control value. In contrast, serum amylase and light microscopy reflected a degree of pancreatitis in a close dose-response pattern to the administered cerulein dose. These findings suggest that ATP depletion--although probably facilitating acinar damage--does not seem to play a causal or primary role in the pathophysiology of acute pancreatitis.


Abulia: a delphi survey of British neurologists and psychiatrists.
Abulia is the relatively uncommon yet debilitating lack of spontaneous, goal-directed behaviour that is seen predominantly with lesions of the basal ganglia and the frontal lobes. We sought to confirm the existence of abulia as an entity recognized by clinicians, to generate a set of items characteristic of the condition, and to see how clinicians differentiate between overlapping disorders. The Delphi technique was used to survey consultant neurologists and psychiatrists at three hospitals in London. The study consisted of two phases: semi- structured interviews of a small group of neurologists and psychiatrists, followed by a survey of a larger group of consultants using postal questionnaires. Both neurologists and psychiatrists recognized abulia to be a distinct clinical entity but its status as a syndrome was unclear. Features such as difficulty in initiating and sustaining spontaneous movements and reduction in emotional responsiveness, spontaneous speech, and social interaction were identified as being characteristic of abulia. The information generated by this study may help to develop a working classification for disorders of diminished drive and motivation, and instruments for clinical assessment and decision making.


Family pathology and anorexia in the Indian context.
Frequent associations have been found between family interaction and anorectic behaviour. Family theorists have viewed anorexia as a manifestation of a dysfunctional family system. We report three families of cases of anorexia (one male and two female) where the symptom was a reflection of family pathology and was being maintained by it. The cases emphasize the need to assess families of anorectics in detail and view them in the cultural context of eating.


A Putative Bacterial ABC Transporter Circumvents the Essentiality of Signal Peptidase.
The type I signal peptidase of Staphylococcus aureus, SpsB, is an attractive antibacterial target because it is essential for viability and extracellularly accessible. We synthesized compound 103, a novel arylomycin-derived inhibitor of SpsB with significant potency against various clinical S. aureus strains (MIC of ~1 µg/ml). The predominant clinical strain USA300 developed spontaneous resistance to compound 103 with high frequency, resulting from single point mutations inside or immediately upstream of cro/cI, a homolog of the lambda phage transcriptional repressor cro These cro/cI mutations led to marked (>50-fold) overexpression of three genes encoding a putative ABC transporter. Overexpression of this ABC transporter was both necessary and sufficient for resistance and, notably, circumvented the essentiality of SpsB during in vitro culture. Mutation of its predicted ATPase gene abolished resistance, suggesting a possible role for active transport; in these bacteria, resistance to compound 103 occurred with low frequency and through mutations in spsB Bacteria overexpressing the ABC transporter and lacking SpsB were capable of secreting a subset of proteins that are normally cleaved by SpsB and instead were cleaved at a site distinct from the canonical signal peptide. These bacteria secreted reduced levels of virulence-associated proteins and were unable to establish infection in mice. This study reveals the mechanism of resistance to a novel arylomycin derivative and demonstrates that the nominal essentiality of the S. aureus signal peptidase can be circumvented by the upregulation of a putative ABC transporter in vitro but not in vivo The type I signal peptidase of Staphylococcus aureus (SpsB) enables the secretion of numerous proteins by cleavage of the signal peptide. We synthesized an SpsB inhibitor with potent activity against various clinical S. aureus strains. The predominant S. aureus strain USA300 develops resistance to this inhibitor by mutations in a novel transcriptional repressor (cro/cI), causing overexpression of a putative ABC transporter. This mechanism promotes the cleavage and secretion of various proteins independently of SpsB and compensates for the requirement of SpsB for viability in vitro However, bacteria overexpressing the ABC transporter and lacking SpsB secrete reduced levels of virulence-associated proteins and are unable to infect mice. This study describes a bacterial resistance mechanism that provides novel insights into the biology of bacterial secretion.


Separation of synthetic oligonucleotide dithioates from monothiophosphate impurities by anion-exchange chromatography on a mono-q column.
A method using a strong anion-exchange liquid-chromatography column, Mono-Q, has been developed for high-resolution analysis and purification of oligonucleotide dithioates, which were synthesized by an automated, solid-phase, phosphorothioamidite chemistry. High-resolution separation of oligonucleotide phosphorodithioates from monothiophosphate impurities was obtained. High-resolution separation was also demonstrated at pH 8. The separation of oligonucleotide dithioates was found to be linearly dependent on the number of sulfurs for the same sequence length. Thiocyanate, SCN-, as eluting anion, can be used to purify oligonucleotides containing a high percentage of phosphorodithioate linkages in lower salt concentrations and provides better separation than chloride as eluting anion.


[Short Review of the History of Radiotherapy for Intraocular Tumours].
For many decades, radiotherapy with its different modalities has proved to be the gold standard in the treatment of benign and malignant intraocular tumours. The various complicated therapeutic developments in this field cover a period of over 100 years and the present year deserves special mention because of the 100th anniversary of the first mention of a successful brachytherapy for a uveal melanoma by R. Deutschmann in Hamburg in 1915.


E-mental health interventions for the treatment and prevention of eating disorders: An updated systematic review and meta-analysis.
E-mental health (digital) interventions can help overcome existing barriers that stand in the way of people receiving help for an eating disorder (ED). Although e-mental health interventions for treating and preventing EDs have been met with enthusiasm, earlier reviews brought attention to poor quality of evidence, and offered solutions to enhance their evidence base. To assess developments in the field, we conducted an updated meta-analysis on the efficacy of e-mental health interventions for treating and preventing EDs, paying attention to whether trial quality and outcomes have improved in recent trials. We also assessed whether user-centered design principles have been implemented in existing digital interventions. Four databases were searched for RCTs of digital interventions for treating and preventing EDs. Thirty-six RCTs (28 prevention- and 8 treatment-focused) were included. Some evidence that study quality improved in recent prevention-focused trials was found. Few trials involved the end-user in the design or development stage of the intervention. Issues with intervention engagement were noted, and 1 in 4 participants dropped out from prevention- and treatment-focused trials. Digital interventions were more effective than control conditions in reducing established risk factors and symptoms in prevention- (g's = 0.19 to 0.43) and treatment-focused trials (g's = 0.29 to 0.69), respectively. Effect sizes have not increased in recent trials. Few trials compared a digital intervention with a face-to-face intervention. Whether digital interventions can prevent ED onset is unclear. Digital interventions are a promising approach to ED treatment and prevention, but improvements are still needed. Three key recommendations are provided. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Thalamic infarctions: differential effects on vestibular function in the roll plane (35 patients).
We determined the subjective visual vertical (SVV), ocular torsion (OT), skew deviation, and lateral head tilt in 35 patients with acute thalamic infarctions (14 paramedian, 17 posterolateral, and four anterior polar) and in five patients with mesodiencephalic hemorrhages to obtain the tonic effects on vestibular function in the roll plane. Eight of 14 paramedian infarctions had complete ocular tilt reaction (OTR) with contraversive head tilt, skew deviation, OT, and SVV tilt. The OTR was due to ischemia of the rostral midbrain tegmentum, including the interstitial nucleus of Cajal (INC), and not to thalamic ischemia. Thus, the INC (and the rostral interstitial nucleus of the medial longitudinal fascicle) is the most rostral brainstem structure mediating eye-head coordination in roll. Eleven of 17 posterolateral infarctions exhibited moderate SVV tilts that were either ipsiversive or contraversive. In these 11 cases, vestibular thalamic nuclei (nucleus ventro-oralis intermedius, nucleus ventrocaudalis externus, and nucleus dorsocaudalis) were involved; infarctions in the remaining six were more ventromedial. Anterior polar infarctions did not affect vestibular function in roll.


Coherency strain and its effect on ionic conductivity and diffusion in solid electrolytes--an improved model for nanocrystalline thin films and a review of experimental data.
A phenomenological and analytical model for the influence of strain effects on atomic transport in columnar thin films is presented. A model system consisting of two types of crystalline thin films with coherent interfaces is assumed. Biaxial mechanical strain ε0 is caused by lattice misfit of the two phases. The conjoined films consist of columnar crystallites with a small diameter l. Strain relaxation by local elastic deformation, parallel to the hetero-interface, is possible along the columnar grain boundaries. The spatial extent δ0 of the strained hetero-interface regions can be calculated, assuming an exponential decay of the deformation-forces. The effect of the strain field on the local ionic transport in a thin film is then calculated by using the thermodynamic relation between (isostatic) pressure and free activation enthalpy ΔG(#). An expression describing the total ionic transport relative to bulk transport of a thin film or a multilayer as a function of the layer thickness is obtained as an integral average over strained and unstrained regions. The expression depends only on known material constants such as Young modulus Y, Poisson ratio ν and activation volume ΔV(#), which can be combined as dimensionless parameters. The model is successfully used to describe own experimental data from conductivity and diffusion studies. In the second part of the paper a comprehensive literature overview of experimental studies on (fast) ion transport in thin films and multilayers along solid-solid hetero-interfaces is presented. By comparing and reviewing the data the observed interface effects can be classified into three groups: (i) transport along interfaces between extrinsic ionic conductors (and insulator), (ii) transport along an open surface of an extrinsic ionic conductor and (iii) transport along interfaces between intrinsic ionic conductors. The observed effects in these groups differ by about five orders of magnitude in a very consistent way. The modified interface transport in group (i) is most probably caused by strain effects, misfit dislocations or disordered transition regions.


Design and Identification of a Novel, Functionally Subtype Selective GABAA Positive Allosteric Modulator (PF-06372865).
The design, optimization, and evaluation of a series of novel imidazopyridazine-based subtype-selective positive allosteric modulators (PAMs) for the GABAA ligand-gated ion channel are described. From a set of initial hits multiple subseries were designed and evaluated based on binding affinity and functional activity. As designing in the desired level of functional selectivity proved difficult, a probability-based assessment was performed to focus the project's efforts on a single subseries that had the greatest odds of delivering the target profile. These efforts ultimately led to the identification of two precandidates from this subseries, which were advanced to preclinical safety studies and subsequently to the identification of the clinical candidate PF-06372865.


Community based schoolchildren's oral health programmes, Kuwait 1985--1998.
To describe the development of children's oral health programmes in Kuwait and present selected results and expected outcomes based on specific markers. To provide a basis for choosing best outcomes to develop public health policy and implement future programmes. Assessment of the health, structural, cost and benefit changes in the oral health sector that resulted from policy decisions and implementation through different approaches in the period 1986--1998. Analysis has provided a basis for selection of appropriate methodologies to be implemented in the country. The regional programme consisting of full immediate prevention coverage with fluoride lozenges, periodic fluoride rinses, multi-operator care teams, flexible and moveable equipment appears to have provided the best potential within the Kuwait context during this period.


[Evaluation of patient absorbed dose management system in percutaneous coronary intervention].
The angiography equipment Infinix Celeve of Toshiba Corp. is a system that estimates patient absorbed dose at the skin by using a dose area product meter. This system performs incidence area compensation, which corresponds to the changes of I.I. size, FID, and FTD. We evaluated the clinical usefulness of patient entrance skin dose management by the dose area product meter of Celeve by verifying the effects of various clinical parameters on absorbed dose. We determined compensation according to the various angles usually used by clinicians, and estimated the absorbed peak dose at the skin. By using the angle compensation of the C arm, the displayed values on the dose area product meter of Celeve could be used for skin doses as they were. The skin absorbed dose was 3.0 Gy or more in 33 of the 332 examples.


Vaginal microbiota in ethnically diverse young women who did or did not develop pelvic inflammatory disease: community-based prospective study.
A lactobacilli-dominated vaginal microbiome may protect against pelvic inflammatory disease (PID), but one dominated by Gardnerella species might increase susceptibility. Not all lactobacilli are equally protective. Recent research suggests that D(-) isomer lactic acid producing lactobacilli (Lactobacillus crispatus, Lactobacillus jensenii and Lactobacillus gasseri) may protect against infection with Chlamydia trachomatis, an important cause of PID. Lactobacillus iners , which produces L(+) isomer lactic acid, may be less protective. We investigated the microbiome in stored vaginal samples from participants who did or did not develop PID during the prevention of pelvic infection (POPI) chlamydia screening trial. Long-read 16S rRNA gene nanopore sequencing was used on baseline vaginal samples (one per participant) from all 37 women who subsequently developed clinically diagnosed PID during 12-month follow-up, and 111 frequency matched controls who did not, matched on four possible risk factors for PID: age <20 versus ≥20, black ethnicity versus other ethnicity, chlamydia positive versus negative at baseline and ≥2 sexual partners in the previous year versus 0-1 partners. Samples from 106 women (median age 19 years, 40% black ethnicity, 22% chlamydia positive, 54% reporting multiple partners) were suitable for analysis. Three main taxonomic clusters were identified dominated by L. iners, L. crispatus and Gardnerella vaginalis. There was no association between a more diverse, G. vaginalis dominated microbiome and subsequent PID, although increased Shannon diversity was associated with black ethnicity (p=0.002) and bacterial vaginosis (diagnosed by Gram stain p<0.0001). Women who developed PID had similar relative abundance of protective D(-) isomer lactic acid producing lactobacilli to women without PID, but numbers of PID cases were small. In the first-ever community-based prospective study of PID, there was no clear association between the vaginal microbiome and subsequent development of PID. Future studies using serial samples may identify vaginal microbial communities that may predispose to PID.


Fast dictionary generation and searching for magnetic resonance fingerprinting.
A super-fast dictionary generation and searching (DGS) algorithm was developed for MR parameter quantification using magnetic resonance fingerprinting (MRF). MRF is a new technique for simultaneously quantifying multiple MR parameters using one temporally resolved MR scan. But it has a multiplicative computation complexity, resulting in a big burden of dictionary generating, saving, and retrieving, which can easily be intractable for any state-of-art computers. Based on retrospective analysis of the dictionary matching object function, a multi-scale ZOOM like DGS algorithm, dubbed as MRF-ZOOM, was proposed. MRF ZOOM is quasi-parameter-separable so the multiplicative computation complexity is broken into additive one. Evaluations showed that MRF ZOOM was hundreds or thousands of times faster than the original MRF parameter quantification method even without counting the dictionary generation time in. Using real data, it yielded nearly the same results as produced by the original method. MRF ZOOM provides a super-fast solution for MR parameter quantification.


Inhibition of bovine heart NAD-specific isocitrate dehydrogenase by reduced pyridine nucleotides: modulation of inhibition by ADP, NAD+, Ca2+, citrate, and isocitrate.
The activity of NAD-dependent isocitrate dehydrogenase from bovine heart was inhibited by NADH (apparent Ki about 4.3 microM) and NADPH (Ki about 9.8 microM) at subsaturating substrate concentrations at pH 7.4. The inhibition by NADH or NADPH was reversed competitively by magnesium isocitrate in the presence of ADP, but not without ADP. Reversal of inhibition by NADH or NADPH with respect to NAD+ was competitive or of the linear mixed type depending on whether ADP was absent or present. ADP3- (0.2 mM) increased the Ki(app) for NADPH from 9.8 to 27.1 microM; further addition of Ca2+ (0.2 mM) raised the Ki(app) to 127 microM. For the modification of NADPH inhibition by ADP, S0.5 for Ca2+ was approximately 48 microM. This compares to the Km for Ca2+ of 0.3-1 microM for the activation of the enzyme without NADPH [Denton, R. M., Richards, D. A., & Chin, J. G. (1978) Biochem. J. 176, 899-906; Aogaichi, T., Evans, J., Gabriel, J., & Plaut, G. W. E. (1980) Arch. Biochem. Biophys. 204, 350-360]. ADP did not affect the Ki for NADH. Magnesium citrate, which was about 100-fold more effective as a positive modifier of the enzyme with ADP than without ADP [Gabriel, J. L., & Plaut, G. W. E. (1983) Fed. Proc., Fed. Am. Soc. Exp. Biol. 42, 2082], reversed competitively the inhibition by NADPH in the presence of ADP, but not without ADP. Magnesium citrate did not reverse NADH inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)


Intravenous branched-chain amino-acid-free solution for the treatment of metabolic decompensation episodes in Spanish pediatric patients with maple syrup urine disease.
Metabolic decompensation episodes (DEs) in Maple Syrup urine disease (MSUD) result in brain accumulation of toxic branched-chain amino acids (BCAAs) and their respective branched-chain α-keto acids that could induce neuroinflammation, disturb brain bioenergetics, and alter glutamate and glutamine synthesis. These episodes require immediate intervention to prevent irreversible neurological damage. Intravenous (IV) administration of BCAA-free solution could represent a powerful alternative for emergency treatment of decompensations. This pediatric series discusses the management of DEs in MSUD patients with IV BCAA-free solution, as an emergency treatment for DEs or as a prophylactic in cases requiring surgery. Clinical evolution, amino acid profile and adverse effects were evaluated. We evaluated the use of BCAA-free solution in 5 DEs in 5 MSUD pediatric patients, all with significantly elevated plasma leucine levels at admission (699-3296 μmol/L) and in 1 episode of risk of DE due to surgery. Leucine normalization was achieved in all cases with resolution or improvement of clinical symptoms following IV BCAA-free solution. The duration of administration ranged from 3-20 days. Administration of IV BCAA-free solution at the beginning of a DE could reverse depletion of the amino acids that compete with BCAAs for the LAT1 transporter, and the observed depletion of alanine, despite IV alanine supplementation. No related adverse events were observed. Administration of standardized IV BCAA-free solution in emergency settings constitutes an important and safe alternative for the treatment of DEs in MSUD, especially in pediatric patients for whom oral or enteral treatment is not viable.


Rosacea, an infectious disease: why rosacea with papulopustules should be considered a demodicosis. A narrative review.
Rosacea and demodicosis are common facial conditions in dermatology practice. While demodicosis is clearly the result of Demodex mite infestation, the pathogenicity of rosacea is still not sufficiently explained, so that it is defined by its symptoms, and not by its cause. It is usually considered as a disease of the immune system associated with neurogenic inflammation triggered by various factors (ultraviolet light, heat, spicy food, alcohol, stress and microorganisms). Its links with demodicosis remain controversial, although there is increasing evidence that Demodex mites may play a key role in the inflammatory process. Indeed, high Demodex densities are observed in nearly all cases of rosacea with papulopustules (PPR) and the papulopustules of rosacea can be effectively treated with topical acaricidal agents. Recent studies suggest that Demodex induces two opposite actions on host immunity: a defensive immune response aimed at eliminating the mite and an immunosuppressive action aimed at favouring its own proliferation. Moreover, the initial defensive immune response is likely diverted towards benefit for the mite, via T-cell exhaustion induced by the immunosuppressive properties of vascular endothelial growth factor, which may also explain the favourable influence that the altered vascular background of rosacea seems to exert on Demodex proliferation. In this review, the evidence for and against a causal role of Demodex in rosacea is discussed, applying three systems traditionally used to attribute causality to a disease (modified Koch criteria, Hill criteria for causality and Rothman model). The findings suggest that PPR can reasonably be attributed to Demodex proliferation, which appears to be a necessary factor in the centre of a causal network in which multiple co-factors interact and influence the occurrence and severity of inflammatory symptoms, from limited (pityriasis folliculorum) to more marked (PPR). PPR could, therefore, be considered as a chronic infection by Demodex mites with associated T-cell exhaustion.


Mortality and its association with chronic and infectious diseases in Mexico: A panel data analysis of the elderly.
This study examines the relationship between chronic and infectious diseases on mortality risks under conditions of accelerated aging.The main hypothesis is that individuals who report both types of diseases experience higher mortality risks than those reporting only chronic diseases. We used a nationally representative sample of 12 128 individuals aged 50 years and over included in the three waves of the Mexican Health and Aging Study. We estimated Cox regression models to assess the combined effect of self-reported chronic and infectious diseases on subsequent mortality. In the period under study there were 2 723 deaths, 22.5% of the baseline sample. Having reported chronic and infectious diseases significantly increases mortality risks compared to having reported only chronic diseases. In a context of socioeconomic inequality and a mixed epidemiological regime it is crucial to understand how diseases combine to generate excess mortality risks among the elderly.


[Clinical observations using the new contraceptive preparation containing gestagen].
31 women aged 26-35 were observed during hormonal contraception with Femovan (in Poland registered as Femoden). The aim of the study was an analysis of effectiveness, influence on menstrual cycles and adverse effects in Femovan users. The conclusions of the study indicated that Femovan is very effective in contraception (Pearl index = 0). It provides good cycle control. It reduced in 50% women nausea and breast tenderness which occurred before starting of contraception. There were not body gain and elevated blood pressure in any women. Acne was reduced in 40% women after 3 months of using.


Validity and reliability of the PowerTap mobile cycling powermeter when compared with the SRM Device.
The SRM power measuring crank system is nowadays a popular device for cycling power output (PO) measurements in the field and in laboratories. The PowerTap (CycleOps, Madison, USA) is a more recent and less well-known device that allows mobile PO measurements of cycling via the rear wheel hub. The aim of this study is to test the validity and reliability of the PowerTap by comparing it with the most accurate (i.e. the scientific model) of the SRM system. The validity of the PowerTap is tested during i) sub-maximal incremental intensities (ranging from 100 to 420 W) on a treadmill with different pedalling cadences (45 to 120 rpm) and cycling positions (standing and seated) on different grades, ii) a continuous sub-maximal intensity lasting 30 min, iii) a maximal intensity (8-s sprint), and iiii) real road cycling. The reliability is assessed by repeating ten times the sub-maximal incremental and continuous tests. The results show a good validity of the PowerTap during sub-maximal intensities between 100 and 450 W (mean PO difference -1.2 +/- 1.3 %) when it is compared to the scientific SRM model, but less validity for the maximal PO during sprint exercise, where the validity appears to depend on the gear ratio. The reliability of the PowerTap during the sub-maximal intensities is similar to the scientific SRM model (the coefficient of variation is respectively 0.9 to 2.9 % and 0.7 to 2.1 % for PowerTap and SRM). The PowerTap must be considered as a suitable device for PO measurements during sub-maximal real road cycling and in sub-maximal laboratory tests.


Three-dimensional hemodynamic design optimization of stents for cerebral aneurysms.
Flow-diverting stents occlude aneurysms by diverting the blood flow from entering the aneurysm sac. Their effectiveness is determined by the thrombus formation rate, which depends greatly on stent design. The aim of this study was to provide a general framework for efficient stent design using design optimization methods, with a focus on stent hemodynamics as the starting point. Kriging method was used for completing design optimization. Three different cases of idealized stents were considered, and 40-60 samples from each case were evaluated using computational fluid dynamics. Using maximum velocity and vorticity reduction as objective functions, the optimized designs were identified from the samples. A number of optimized stent designs have been found from optimization, which revealed that a combination of high pore density and thin struts is desired. Additionally, distributing struts near the proximal end of aneurysm neck was found to be effective. The success of the methods and framework devised in this study offers a future possibility of incorporating other disciplines to carry out multidisciplinary design optimization.


Analysis of intrinsic pH, soluble solids and buffer effect of non-alcoholic drinks.
The aim of the present study was to determine in vitro the erosive capacity of different common drinks employing intrinsic pH, soluble solids and buffer effect at pH 5.5 and pH 7.0 as end-points. Fifty- two drinks of mass consumption were selected and grouped according to type into 3 groups: 1: Juices (n = 23); 2: soy beverages (n = 18); 3: carbonated drinks (n = 11). The mean and standard deviation were calculated for each drink and for each group of drinks. The statistical analysis of the data was performed by Analysis of Variance (ANOVA) and Tukey's test for multiple comparisons. Statistical significance was set at p < or = 0.05. The data showed that the 3 groups exhibited initial acid pH values. Natural juices had the greatest buffer effect. The soluble solids, expressed as Brix Grades, showed statistically significant differences between the regular and light forms of carbonated and soy beverages. The light and regular forms of the drinks included in the study failed to show statistically significant differences at pH 5.5 and pH 7.0.


An effective model for predicting serum albumin level in hemodialysis patients.
Patients on hemodialysis (HD) are known to be at an increased risk of mortality. Hypoalbuminemia is one of the most important risk factors of death in HD patients, and is an independent risk factor for all-cause mortality that is associated with cardiac death, infection, and Protein-Energy Wasting (PEW). It is a clinical challenge to elevate serum albumin level. In addition, predicting trends in serum albumin level is effective for personalized treatment of hypoalbuminemia. In this study, we analyzed a total of 3069 records collected from 314 HD patients using a machine learning method that is based on an improved binary mutant quantum grey wolf optimizer (MQGWO) combined with Fuzzy K-Nearest Neighbor (FKNN). The performance of the proposed MQGWO method was evaluated using a series of experiments including global optimization experiments, feature selection experiments on open data sets, and prediction experiments on an HD dataset. The experimental results showed that the most critical relevant indicators such as age, presence or absence of diabetes, dialysis vintage, and baseline albumin can be identified by feature selection. Remarkably, the accuracy and the specificity of the method were 98.39% and 96.77%, respectively, demonstrating that this model has great potential to be used for detecting serum albumin level trends in HD patients.


Exploring the medical need for alternate site testing. A clinician's perspective.
The ability of the clinician to make rapid and precise decisions is the cornerstone of cost-effective patient care. Alternate site testing can provide rapid information to clinicians in emergency departments and critical care units. This can increase cost-effectiveness of treatment by shortening the length of hospital stays and reducing unnecessary treatment. Currently available alternate site coagulation methods allow for much more rapid achievement of effective and safe levels of anticoagulation. Potential alternate site methods of measurement of cardiac enzymes could reduce admissions to critical care units for chest pain and improve assessment of coronary artery reperfusion.


[Construction of a cDNA library of Schistosoma japonicum].
The template mRNA was extracted from Schistosoma japonicum. The first strand of cDNA was synthesized by AMV-reverse transcriptase. The second strand cDNA was first digested by RNase H to remove mRNA and was then synthesized by AMV-reverse transcriptase, T4-DNA polymerase. Sizing of cDNA was applied on a NACS column to remove small fragments of less than 1 kb. Homopolymeric tailing of vector (pUC18) was done with dGTP and DNA terminal transferase and tailing of the cDNA with dCTP was carried out under the same conditions. After annealing, the plasmids with cDNA were transformed into E. coli MC1061. The efficiency of cloning was about 10(4)/micrograms mRNA with 30% of the transformants having the inserts of cDNA (Figs. 1-2).


Loss of the SV2-like protein SVOP produces no apparent deficits in laboratory mice.
Neurons express two families of transporter-like proteins - Synaptic Vesicle protein 2 (SV2A, B, and C) and SV2-related proteins (SVOP and SVOPL). Both families share structural similarity with the Major Facilitator (MF) family of transporters. SV2 is present in all neurons and endocrine cells, consistent with it playing a key role in regulated exocytosis. Like SV2, SVOP is expressed in all brain regions, with highest levels in cerebellum, hindbrain and pineal gland. Furthermore, SVOP is expressed earlier in development than SV2 and is one of the neuronal proteins whose expression declines most during aging. Although SV2 is essential for survival, it is not required for development. Because significant levels of neurotransmission remain in the absence of SV2 it has been proposed that SVOP performs a function similar to that of SV2 that mitigates the phenotype of SV2 knockout mice. To test this, we generated SVOP knockout mice and SVOP/SV2A/SV2B triple knockout mice. Mice lacking SVOP are viable, fertile and phenotypically normal. Measures of neurotransmission and behaviors dependent on the cerebellum and pineal gland revealed no measurable phenotype. SVOP/SV2A/SV2B triple knockout mice did not display a phenotype more severe than mice harboring the SV2A/SV2B gene deletions. These findings support the interpretation that SVOP performs a unique, though subtle, function that is not necessary for survival under normal conditions.


New cases of trepanations from the 5th to 3rd millennia BC in Southern Russia in the context of previous research: Possible evidence for a ritually motivated tradition of cranial surgery?
It is a big challenge to diagnose the motives behind trepanations in prehistoric crania. Surgical-therapeutic attempts may be apparent by the presence of fractures, however, ritual or nonmedical motives are rarely supported by visible evidence in the bones. This article presents data on the trepanations of several individuals from South Russia dating to the Eneolitic and Bronze Age that may indicate a ritual procedure. In these crania an operation was performed in the identical location, the midline, furthermore in one of the most dangerous places, on the obelion. No evidence for traumatic or other pathological reasons for performing the operations was observable. Investigations of two nearby areas of South Russia revealed 13 individuals showing complete perforations in the midline of the cranium. Another one, displaying a depression in the same place, primarily diagnosed as an incomplete trepanation, is discussed considering all differential diagnoses. The trepanations were investigated macroscopically, by plain radiography and computed tomography. The lesions were described in detail, including data on technique, position, size, shape, state of healing, and complications. Males and females received the operation between the age of 10 years and mature/senile age. Only grooving and scraping techniques were used and their application differed between sexes. The majority of the patients survived the intervention for a long time. The region of Southern Russia seems to be a center for special trepanations performed by skilled surgeons, the specific position of the perforations implying more a ritual than therapeutic reason for trepanning. Am J Phys Anthropol 160:665-682, 2016. © 2016 Wiley Periodicals, Inc.


Molecular evolution of miraculin-like proteins in soybean Kunitz super-family.
Miraculin-like proteins (MLPs) belong to soybean Kunitz super-family and have been characterized from many plant families like Rutaceae, Solanaceae, Rubiaceae, etc. Many of them possess trypsin inhibitory activity and are involved in plant defense. MLPs exhibit significant sequence identity (~30-95%) to native miraculin protein, also belonging to Kunitz super-family compared with a typical Kunitz family member (~30%). The sequence and structure-function comparison of MLPs with that of a classical Kunitz inhibitor have demonstrated that MLPs have evolved to form a distinct group within Kunitz super-family. Sequence analysis of new genes along with available MLP sequences in the literature revealed three major groups for these proteins. A significant feature of Rutaceae MLP type 2 sequences is the presence of phosphorylation motif. Subtle changes are seen in putative reactive loop residues among different MLPs suggesting altered specificities to specific proteases. In phylogenetic analysis, Rutaceae MLP type 1 and type 2 proteins clustered together on separate branches, whereas native miraculin along with other MLPs formed distinct clusters. Site-specific positive Darwinian selection was observed at many sites in both the groups of Rutaceae MLP sequences with most of the residues undergoing positive selection located in loop regions. The results demonstrate the sequence and thereby the structure-function divergence of MLPs as a distinct group within soybean Kunitz super-family due to biotic and abiotic stresses of local environment.


A Temperature-Controlled, Conductive PANI@CNFs/MEO2 MA/PEGMA Hydrogel for Flexible Temperature Sensors.
Electrically conductive, yet stimuli-responsive hydrogels are highly desirable for many technological applications. However, the discontinuous conductivity of hydrogels during the response process has become a bottleneck that limits their application. To overcome this constraint, a linearly tunable, electrically conductive hydrogel is prepared using in-situ polymerized polyaniline (PANI) on a CNFs/MEO2 MA/PEGMA hydrogel (PANI@CMP hydrogel) substrate. The PANI@CMP hydrogel exhibits temperature-tunable electrical conductivity due to the liner relationship between thermosensitivity and temperature of the CMP hydrogel substrate. Furthermore, the stiffness and elasticity of the resultant hydrogel after PANI introduction is enhanced via physical interactions, and the compression load is improved by 42%. A highly sensitive temperature sensor is therefore fabricated with PANI@CMP hydrogel as the flexible induction element, and this sensor achieves temperature monitoring from 20 to 60 °C. This new temperature-controllable conductive hydrogel has excellent mechanical properties, showing great potential for applications in flexible smart sensors, conductive fillers, and medical devices.


Acute lower respiratory infections: real-world evidence of antibiotic prescription pattern and costs from a large administrative Italian database.
This observational retrospective analysis aimed to describe antibiotic prescription pattern in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and community-acquired pneumonia (CAP) and their costs, from the Italian National Health Service perspective. From the ReS database, a cross-linkage of Italian healthcare administrative databases through a unique anonymous code allowed to select subjects aged ≥12 years, supplied with at least an antibacterial for systemic use (ATC code: J01) from 01/01/2017 to 12/31/2017 and evaluable until the end of 2018. Prescriptions of different antibiotics on the same date were excluded. The prescription pattern was assessed for patients with an AECOPD (aged ≥50) or a CAP event (aged ≥12) in 2017. A 30-day cost analysis after the antibacterial supply and according to absence/presence (15 days before/after the supply) of AECOPD/CAP hospitalization was performed. In 2017, among patients aged ≥12 (~5 million), 1,845,268 were supplied with ≥1 antibacterial (37.2%). Antibacterial prescriptions potentially related to AECOPD were 39,940 and 4,059 to CAP: quinolones were the most prescribed (37.2% and 39.0%, respectively), followed by third-generation cephalosporins (25.5%; 27.5%), penicillins (15.4%; 14.9%), and macrolides (14.4%; 11.3%); the 30-day mean cost was €709 and €2,889. An association AECOPD/CAP-antibacterial supply costed more when the hospitalization occurred 15 days after the antibiotic supply (€5,006 and €4,966, respectively). Findings confirmed the very high use of antimicrobials in Italy and highlighted the urgent need of improving current prescribing practices and developing new molecules, to stop the incessant spread of antimicrobial resistance and related socioeconomic impacts.


Fatality due to severe Salmonella enteritis associated with acute renal failure and septicemia.
A 66-year-old man was hospitalized for abdominal pain and diarrhea of more than 10 times a day. He had been under regular medication with prednisolone for rheumatoid arthritis. On admission, laboratory data and clinical examination indicated inflammation, dehydration, acute renal failure with a high level of serum musculogenic enzyme (creatine kinase), and ileus. Salmonella enteritidis was isolated from his fecal and blood samples. The patient died within 24 hours after admission, and autopsy showed hemorrhagic necrotic enteritis localized to the ileum. Enterocolitis due to Salmonella enteritidis, which is usually an acute self-limited gastrointestinal illness, may occasionally be a serious and lethal disease.


The RAD2 domain of human exonuclease 1 exhibits 5' to 3' exonuclease and flap structure-specific endonuclease activities.
The RAD2 family of nucleases includes human XPG (Class I), FEN1 (Class II), and HEX1/hEXO1 (Class III) products gene. These proteins exhibit a blend of substrate specific exo- and endonuclease activities and contribute to repair, recombination, and/or replication. To date, the substrate preferences of the EXO1-like Class III proteins have not been thoroughly defined. We report here that the RAD2 domain of human exonuclease 1 (HEX1-N2) exhibits both a robust 5' to 3' exonuclease activity on single- and double-stranded DNA substrates as well as a flap structure-specific endonuclease activity but does not show specific endonuclease activity at 10-base pair bubble-like structures, G:T mismatches, or uracil residues. Both the 5' to 3' exonuclease and flap endonuclease activities require a divalent metal cofactor, with Mg(2+) being the preferred metal ion. HEX1-N2 is approximately 3-fold less active in Mn(2+)-containing buffers and exhibits <5% activity in the presence of Co(2+), Zn(2+), or Ca(2+). The optimal pH range for the nuclease activities of HEX1-N2 is 7.2-8.2. The specific activity of its 5' to 3' exonuclease function is 2.5-7-fold higher on blunt end and 5'-recessed double-stranded DNA substrates compared with duplex 5'-overhang or single-stranded DNAs. The flap endonuclease activity of HEX1-N2 is similar to that of human flap endonuclease-1, both in terms of turnover efficiency (k(cat)) and site of incision, and is as efficient (k(cat)/K(m)) as its exonuclease function. The nuclease activities of HEX1-N2 described here indicate functions for the EXO1-like proteins in replication, repair, and/or recombination that may overlap with human flap endonuclease-1.


An unusual presentation of carcinoma stomach.
Symptomatic gastric malignancy usually presents with symptoms which mimic peptic ulcer disease.Usual presenting features include weight loss and abdominal pain. Other symptoms include nausea, vomiting, dysphagia, melena and early satiety. Gastric malignancy presenting with hemetemesis, macular skin lesions of DIC and low backache due to bone metastasis from the primary is rare. Also bone metastasis in gastric cancer in the absence of hepatic metastasis is also rare.


Acanthamoeba keratitis related to contact lens use in a tertiary hospital in China.
To report the clinical and microbiological features of Acanthamoeba keratitis (AK) related to contact lens use in a tertiary hospital in China. In this retrospective study, the medical results of 61 cases of AK related to contact lens use from January 2000 to December 2017 were reviewed. The data included patients' demographics, lens type, history, risk factors, disease stages, corneal scraping and culture reports, and treatments. Moreover, genotypic identification of some of the isolates was carried out with a PCR assay and sequence analysis of the 18S ribosomal DNA gene. There were 64 eyes included in the study. A total of 32.8% of the patients wore soft contact lenses, and 67.2% of patients used overnight orthokeratology. In the cases (20 eyes) in the early stage, 65% (13 eyes) had positive results according to Giemsa-stained smears, and 0.9% sodium chloride (NaCl) wet mounts revealed trophozoites in 7 eyes (35%). Six eyes (30%) were diagnosed by confocal microscopy combined with clinical signs. In the orthokeratology patients, 87.8% (36/41) rinsed their lenses and/or cases with tap water; 55% of soft-lens wearers wore their lenses while showering. The genotype of 9 isolates was determined, and all the strains belonged to genotype T4. In the orthokeratology group, the number of patients who required therapeutic penetrating keratoplasty after 2005 was less than that before 2005 (chi-square test, χ2 = 4.209, P = 0.04). More than two-thirds of the cases were associated with orthokeratology. Examinations with Giemsa-stained smears, 0.9% NaCl wet mounts and confocal microscopy should be performed for patients who are highly suspected of having early-stage AK to help with early diagnosis. In the orthokeratology group, the rate of therapeutic keratoplasty after 2005 was less than that before 2005.


Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-γ in a nitric oxide-dependent manner.
Immunodeficiency in chronic granulomatous disease (CGD) is well characterized. Less understood are exaggerated sterile inflammation and autoimmunity associated with CGD. Impaired recognition and clearance of apoptotic cells resulting in their disintegration may contribute to CGD inflammation. We hypothesized that priming of macrophages (Ms) with IFN-γ would enhance impaired engulfment of apoptotic cells in CGD. Diverse M populations from CGD (gp91(phox)(-/-)) and wild-type mice, as well as human Ms differentiated from monocytes and promyelocytic leukemia PLB-985 cells (with and without mutation of the gp91(phox)), demonstrated enhanced engulfment of apoptotic cells in response to IFN-γ priming. Priming with IFN-γ was also associated with increased uptake of Ig-opsonized targets, latex beads, and fluid phase markers, and it was accompanied by activation of the Rho GTPase Rac. Enhanced Rac activation and phagocytosis following IFN-γ priming were dependent on NO production via inducible NO synthase and activation of protein kinase G. Notably, endogenous production of TNF-α in response to IFN-γ priming was critically required for inducible NO synthase upregulation, NO production, Rac activation, and enhanced phagocytosis. Treatment of CGD mice with IFN-γ also enhanced uptake of apoptotic cells by M in vivo via the signaling pathway. Importantly, during acute sterile peritonitis, IFN-γ treatment reduced excess accumulation of apoptotic neutrophils and enhanced phagocytosis by CGD Ms. These data support the hypothesis that in addition to correcting immunodeficiency in CGD, IFN-γ priming of Ms restores clearance of apoptotic cells and may thereby contribute to resolution of exaggerated CGD inflammation.