Radiation-induced changes in cellularity and proliferation in human oral mucosa.
To quantify the oral mucosal cell density and proliferation rate during conventional radiotherapy of head-and-neck tumors and to compare these parameters with clinical scoring of oral mucositis. Between 1996 and 1999, 22 patients were included in this study. Mucosal biopsies were taken before or during the radiotherapy course (5 x 2 Gy/wk). Biopsies were incubated in vitro with tritiated thymidine immediately after excision to label DNA-synthesizing cells. Epithelial cell density followed a biphasic radiation response. A steep decrease to about 50% of the preirradiation value (1000 cells/mm epithelium) during Week 1 was followed by a more gradual loss to about 400 cells at the end of treatment. The initial phase was based on the depression of proliferation, with 5-10 labeled cells/mm at the end of Week 1 vs. 60 labeled cells/mm in controls. Subsequently, proliferation was partially restituted at 20 labeled cells/mm. A significant difference in cell numbers was seen between Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Grade 0 (approximately 850 cell/mm) and Grade 2 (325/mm) or Grade 3 (370/mm). No significant differences were observed between reaction grades 1, 2, and 3. Conventionally fractionated radiotherapy induces a rapid suppression in cell production in Week 1, which results in a prompt reduction in cell numbers. Subsequently, a partial restoration of proliferation significantly reduces the rate of cell loss. These processes clearly precede the clinical response. Regeneration, defined as restoration of cellularity, is already under way when the maximal clinical response is observed. Clinical reaction grading corresponds poorly to cellular density measures during conventional fractionation.


Feeding frequencies of nestling blue tits (Parus caeruleus): costs, benefits and a model of optimal feeding frequency.
1. To examine the ultimate factors determining the frequency with which male and female blue tits (Parus caeruleus) feed their nestlings, I manipulated the brood sizes of 34 pairs breeding in Wytham Woods, England, and recorded automatically the number of visits when the young were 11-13 days of age. At this time adults were caught and weighed and the nestlings weighed. 2. The number of visits/brood increased linearly with brood size, with no evidence of an upper limit to brood feeding frequency. The number of visits·nestlings-1·day-1 decreased from 138 to 108 as brood size increased from 3 to 6, but levelled off at 68-87 visits/nestling as brood size increased from 8 to 15. 3. Female weight-loss during the nestling period increased linearly as the feeding frequency of the brood increased: those females were lightest that fed their young most often; this is of some significance since I previously showed that the lightest females are least likely to survive to the following year. The correlations of feeding frequency with brood size and feeding frequency with female weight are sufficient to account for the commonly observed correlation of brood size and female weight. No relationship between feeding frequency and male weight dynamics was apparent. Feeding frequency of the brood increased as mean nestling weight decreased. Apparently, parents compensate, in part, for low nestling weight by increasing feeding frequency. Low nestling weight, in turn, has proven detrimental to post-fledging survival. 4. Lack's (1947, 1954) hypothesis, that the decline in visits/nestling as brood size increases reflects the inability of parents to sustain high brood feeding rates, is refuted by the observations made in this and a large number of other studies. Royama's (1966) hypothesis that the observed decline in visits/nestling reflects a decrease in energy needed to maintain homeothermy, receives some support. Behavioral and physiological studies, however, suggest that the "Royama effect" is limited to small broods (c. four or fewer young). 5. I propose, instead, a model of optimal feeding frequency, which accounts for observations made by myself and others, and which incorporates Royama's hypothesis as well. The model assumes that parents optimize their investment in their young. On the one hand, an increase in feeding frequency means more food for the young, which enhances offspring survival ("benefit"); on the other hand, increased feeding frequency is "costly" to the parents (reduces parental survivorship). Natural selection favors breeding individuals that maximize the difference between benefits (to the offpsring) and costs (to the parents). The model accounts for many aspects of blue tit reproductive biology, including the observed relationship between nestling weight and brood size and the observation that parent reproductive costs increase with brood size.


Role of Chemotherapy and Radiation Therapy in the Management of Gastric Adenocarcinoma.
Gastric adenocarcinoma is the fifth most common cancer worldwide and is often diagnosed at a late stage with nearly 50% of patients having locally advanced, unresectable, or metastatic disease at the time of presentation. Efforts to improve outcomes in patients with resected and unresectable gastric cancer with various chemotherapy and radiation regimens are ongoing. Appropriate evaluation and management is often not straightforward and requires the input of a multidisciplinary team. There is no consensus as to the best approach for treatment of gastric cancer; however, the available data and our institutional approach to the management of gastric cancer are discussed.


Products of Cu(II)-catalyzed oxidation of the N-terminal fragments of alpha-synuclein in the presence of hydrogen peroxide.
Reactive oxygen species (ROS) may provide the covalent modifications of amino acid residues in proteins, formation of protein-protein cross-linkages, and oxidation of the protein backbone resulting in protein fragmentation. In an attempt to elucidate the products of the copper(II)-catalyzed oxidation of the (1-17), (1-28), (1-39) and (1-39)(A30P) fragments of alpha-synuclein, the high performance liquid chromatography (HPLC) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) methods and Cu(II) /hydrogen peroxide as a model oxidizing system were employed. Peptide solution (0.50 mM) was incubated at 37 degrees C for 24 h with metal:peptide:hydrogen peroxide molar ratio 1:1:4 in phosphate buffer, pH 7.4. Oxidation targets for all peptide studied are the methionine residues (M(1), M(5)). Incubation 24 h of the (1-28), (1-39) and (1-39)(A30P) fragments in aerobic conditions lead to the oxidation of one methionine residue to methionine sulfoxide. Reaction of hydrogen peroxide with all fragments of alpha-synuclein resulted in oxidation of two methionine residues (M(1), M(5)) to methionine sulfoxides. For the Cu(II):peptide:hydrogen peroxide 1:1:4 molar ratio systems the further oxidation of methionine residues to sulfone was observed. The cleavage of the peptide bond M(1)-D(2) for all peptides studied was observed as metal binding residues. For the (1-39) and (1-39)(A30P) fragments of alpha-synuclein the molecular ions with lower molecular masses (A(11)-Y(39), E(13)-Y(39)) were also detected.


Novel Radiographic Parameters for Posterior Atlantoaxial Dislocation Secondary to Os Odontoideum and Its Clinical Significance.
To explore correlations of 3 novel radiographic parameters with myelopathy induced by posterior atlantoaxial dislocation (PAAD) secondary to os odontoideum (OO) and assess their reproducibility. Of the 51 patients with OO with PAAD enrolled in this study, 28 developed PAAD-induced myelopathy (myelopathy group), and the other 23 patients had no myelopathy (control group). Neurologic function was evaluated by the neurologic function rating system and the Japanese Orthopaedic Association score system. Three novel radiographic parameters (OP [median sagittal diameter of the spinal canal from the posteroinferior edge of the ossicle to the anterosuperior edge of the spinous process of C2]/C4 SAC [space available for spinal cord] ratio, C1 posterior inclination angle, and posterior dislocation index) were measured by lateral cervical dynamic radiography. Their correlations with neurologic function were analyzed, and their reproducibility was assessed by the intraclass correlation coefficient (ICC). In addition, receiver operating characteristic curve analysis was performed. A significant correlation was observed between the OP/C4 SAC ratio and the neurologic function (P < 0.01), and between the C1 posterior inclination angle and the neurologic function (P < 0.01). Furthermore, their interobserver and intraobserver reliability was excellent (ICC ≥ 0.912). Receiver operating characteristic curve analysis showed that the optimal threshold value relating to myelopathy of the OP/C4 SAC ratio and C1 posterior inclination angle was 0.93 and 20°, respectively. The OP/C4 SAC ratio and the C1 posterior inclination angle seem to be 2 effective and objective radiographic parameters for relating myelopathy in patients with OO with PAAD. When the OP/C4 SAC ratio is <0.93 and/or the C1 posterior inclination angle is >20°, the risk of developing myelopathy should be highly suspected in patients with OO with PAAD.


Using community science data to assess the association between urbanization and the presence of invasive Aedes species in Hungary.
Urbanization can be a significant contributor to the spread of invasive mosquito vector species, and the diseases they carry, as urbanized habitats provide access to a great density of food resources (humans and domestic animals) and offer abundant breeding sites for these vectors. Although anthropogenic landscapes are often associated with the presence of invasive mosquito species, we still have little understanding about the relationships between some of these and the built environment. This study explores the association between urbanization level and the occurrence of invasive Aedes species, specifically Aedes albopictus, Aedes japonicus, and Aedes koreicus, in Hungary, using data from a community (or citizen) science program undertaken between 2019 and 2022. The association between each of these species and urbanized landscapes within an extensive geographic area was found to differ. Using the same standardized approach, Ae. albopictus showed a statistically significant and positive relationship with urbanization, whereas Ae. japonicus and Ae. koreicus did not. The findings highlight the importance of community science to mosquito research, as the data gathered using this approach can be used to make qualitative comparisons between species to explore their ecological requirements.


Scanning electron microscopy of podocytes of the renal glomerulus of rats with nephrotoxic serum nephritis.
Nephrotoxic serum nephritis was produced in rats by intraperitoneal injections of rabbit nephrotoxic serum. Heterologous and autologous phases of nephritis were demonstrated by immunofluorescence and ultrastructural studies. Scanning electron microscopy showed changes in the surface of the podocytes, swelling of the arm-like cytoplasmic processes, and disappearance of the pedicles. The podocyte alterations are discussed.


Rapidly progressive glomerulonephritis in a patient with angioimmunoblastic T-cell lymphoma: a rare autopsy case showing IgA vasculitis and cylinder-like deposits.
Angioimmunoblastic T-cell lymphoma (AITL), a hematological malignancy, originates from follicular helper T cells. The primary site of AITL is the lymph nodes, but extranodal presentation is frequent in patients with advanced stages. Here, we report a rare case of a patient with AITL presenting with rapidly progressive glomerulonephritis (RPGN). The patient underwent computed tomography, which showed systemic lymph node swelling. RPGN was noted at the time of admission. Livedo was observed in the lower limbs with purpura on the foot. The patient was diagnosed with AITL based on lymph node biopsy. Skin biopsy revealed vasculitis with immunoglobulin A (IgA) deposits. Renal biopsy revealed endocapillary proliferative glomerulonephritis with massive subendothelial deposits and intraluminal thrombi. Immunofluorescence showed IgA, IgG, and complement component 3c-predominant granular staining pattern in the capillary and mesangial areas. Electron micrographs demonstrated dense cylindrical-like deposits in the subendothelial space. Chemotherapy drugs were administered, but the patient's respiratory distress increased until death. Upon autopsy, membranoproliferative glomerulonephritis and extensive necrotizing cellular crescent formation were observed in the glomeruli. Taken together, this case is a rare combination of AITL and RPGN showing both cylinder-like deposits suggestive of cryoglobulinemic glomerulonephritis (CN) and IgA vasculitis.


COVID-19-associated psychosis: A systematic review of case reports.
To describe the comorbidities, presentations, and outcomes of adults with incident psychosis and a history of COVID-19. We completed a descriptive systematic review of case reports according to PRISMA guidelines, including cases of adult patients with incident psychosis and antecedent or concurrent COVID-19. We extracted patient demographics, comorbidities, clinical course, and outcomes, and assessed cases for quality using a standardized tool. Of 2396 articles, we included 40 reports from 17 countries, comprising 48 patients. The mean age of patients was 43.9 years and 29 (60%) were males. A total of 7 (15%) had a documented psychiatric history, 6 (13%) had a substance use history and 11 (23%) had a comorbid medical condition. Delusions were the most common (44 [92%]) psychiatric sign and psychosis lasted between 2 and 90 days. A total of 33 (69%) patients required hospitalization to a medical service and 16 (33%) required inpatient psychiatric admission. The majority (26 [54%]) of cases did not assess for delirium and 15 (31%) cases were judged to be of high risk of bias. Despite the growing awareness of COVID-19's association with incident psychosis at a population level, cases of COVID-19-associated psychosis often lacked clinically relevant details and delirium was frequently not excluded. PROSPERO registration number: CRD42021256746.


To Study the Role of FNAC in Pre-operative Diagnostic Work Up and Management in Parotid Tumours.
Parotid gland is an important major salivary gland connected to the oral cavity. Salivary gland tumours are infrequent around less than 3% of head and neck tumours. Parotid gland is the most common site for the occurrence of salivary tumors. They are heterogeneous group of neoplasm characterized by the varying histological features and clinical behaviour. In our study we have examined the role of FNAC for preoperative diagnostic and management. We have concluded that Fine needle aspiration cytology is advocated routinely to know the type and nature of the tumour as an important pre-operatively diagnostic work up. It helps in preoperative identification of type of tumour neoplastic or benign, preoperative counselling of patient, planning of management of tumour, and preparing the patient and the surgical team for the more extensive procedure generally required for a high grade malignancy.


Comparing SF-36 scores across three groups of women with different health profiles.
The widespread use of the Medical Outcomes Study (MOS) 36-item Short-Form Health Survey (SF-36) facilitates the comparison of health-related quality of life (HRQL) across independent studies. To compare the scores of eight scales and two summary scales of the SF-36 across participants in the Women's Healthy Eating and Living (WHEL) trial, the Women's Health Initiative-Dietary Modification trial (WHI-DM), and the MOS, and to illustrate the use of effect sizes for interpreting the importance of group differences. WHEL and WHI-DM are both multi-center dietary interventions; only data from the UC Davis sites were used in our study. WHEL participants had a recent history of breast cancer, WHI-DM participants were healthy, postmenopausal women, and women in the MOS had a history of hypertension, diabetes, heart disease, or depression. General linear models were used to identify statistically significant differences in scale scores. Meaningful differences were determined by effect sizes computed using a common within-group standard deviation (SD) and SDs from normative data. After adjusting for age and marital status, SF-36 scores for the WHI-DM and WHEL samples were similar and both had statistically significantly higher scores than the MOS sample. Relative to the WHEL or WHI-DM studies, MOS scores for scales related to the physical domain were clearly meaningfully lower whereas scale scores related to the mental health domain were potentially meaningfully lower. The HRQL of breast cancer survivors is comparable to that of healthy women and better than that of women with chronic health conditions, particularly with respect to physical health. This study illustrated the use of ranges of effects sizes for aiding the interpretation of SF-36 scores differences across independent studies.


Irritancy and anti-inflammatory activity of bis(eta 5-cyclopentadienyl)titanium(IV) complexes in rats.
Dichloro-bis(eta 5-cyclopentadienyl)titanium(IV) and some related complexes were compared with cis-dichlorodiammineplatinum(II) in rats for acute anti-inflammatory activity against carrageenan paw oedema, anti-arthritic activity against developing and established adjuvant-induced polyarthritis, immunosuppressant activity in a local graft-vs. host assay, irritant effects at sites of administration (paw, skin, peritoneum) and nephro- and gastro-toxicities. These titanium complexes, like cisplatin and its hydrolysis products, in vivo exhibited both anti-inflammatory and anti-arthritic activity as well as immunosuppressant effects. Nephro- and gastro-toxicity were much less severe than in rats given platinum complexes. In vitro they selectively inhibited [3H]thymidine incorporation by isolated thymocytes and prevented the germination of radish seeds. When given intraperitoneally, the anti-inflammatory activity may partly be due to a counter-irritant phenomenon since the titanium derivatives elicited an acute peritoneal effusion if they were injected towards the omentum. However, when injected subcutaneously or applied in dimethylformamide or dimethylsulfoxide to the skin, they manifested both anti-inflammatory and anti-arthritic activity without irritancy or much local skin damage. They might therefore have the potential of being useful drugs, especially if released slowly.


[Physical therapy and occupational therapy in German palliative care: Where do we stand?]
Physical therapy (PT) and occupational therapy (OT) as supportive forms of treatment in palliative care, together with other treatment measures, can create participation for seriously ill patients in the form of a life that is as autonomous as possible until the end of life. However, specially trained staff are needed for the care of palliative patients in order to do justice to the clients' special life situation. In Germany, no corresponding survey on the subject has so far been conducted. So it is unclear to what extent PT and OT are offered in palliative care structures in this country, which tasks are assigned to the respective professional groups, and what the level of knowledge is that caregivers have about treatment options. Compilation of an overview of the provision, need and use of PT and OT in the various areas of palliative care in Germany. If there is a lack of provision, the reasons for this will be identified. In this cross-sectional survey, a self-designed 9-item questionnaire was sent out to a total of 260 hospices, 323 palliative care units and 304 specialized outpatient palliative care services (SOPC) listed on the homepage of the German Society for Palliative Medicine (DGP). The respondents' answers were analysed using a purely descriptive approach. The response rate was 439 (49.5%). A total of 434 questionnaires (49%) were included in the analysis. A heterogeneous distribution of PT and OT offers between outpatient, inpatient, and hospice palliative care can be seen, with the outpatient area showing a significantly fewer offerings. 29% of the SOPC teams can offer neither PT nor OT. This is mostly due to a shortage of skilled workers or a lack of funding opportunities. The different areas of responsibility of physiotherapists and occupational therapists are known to the majority of respondents (hospice 87%, palliative care unit 83%, SOPC 81%) and are also reflected in the distribution of tasks between the two professional groups. Especially palliative care units and SOPC teams state that they would like to offer more PT and OT (palliative care units 42% more PT and 58% more OT; SOPC 65% more PT and 50% more OT). This cross-sectional survey is the first of its kind to provide an overview of the PT and OT offerings in the different sectors of German palliative care. In a comparison of the two forms of therapy, occupational therapists are used less frequently than physiotherapists. An international comparison of the study situation also shows that the use of OT in palliative care, in particular, has not yet been implemented satisfactorily. Outside Germany, the main reasons for this are a shortage of specialists and a lack of knowledge about the tasks of OT. PT and OT are frequently used treatment options in all areas of German palliative care. In order to better classify structural problems in care, further differentiated surveys should be conducted. Furthermore, a better knowledge base should be created through research and information activities of both professional groups in palliative care.


The investigation of total PSA, free PSA, and free/total PSA ratio in patients with liver cirrhosis patients according to Child-Pugh score.
To investigate the total prostate-specific antigen (tPSA), free PSA (fPSA), and free/total PSA (fPSA/tPSA) ratio in patients with liver cirrhosis (LC) according to the severity of hepatic insufficiency. Eighty-two male patients with LC were studied. The severity of liver disease was categorized by Child-Pugh score (Child-Pugh A, B, and C). Forty-two age-matched healthy subjects were used as a control group. The tPSA, fPSA, fPSA/tPSA ratio, total prostate volume (TPV), total testosterone (TT), and total protein (TP) were measured. The LC group was compared with the control group in terms of these parameters. In addition, intra-comparison and inter-comparison was made between all the Child-Pugh groups and normal subjects, in terms of these parameters. The tPSA and fPSA levels in LC cases, Child-Pugh A, Child-Pugh B, and Child-Pugh C groups were significantly decreased compared with the control group. The ratio of fPSA/tPSA in the LC subjects and Child-Pugh A groups significantly increased compared with the control group. TT, TP levels, and TPV in patients with LC were significantly lower compared with the control group and the results were significantly correlated with the Child-Pugh score. The present study reveals that tPSA and fPSA were decreased in patients with LC in comparison to healthy subjects in terms of 3 mechanisms. First, it might be due to shrunken prostatic volume. Second, it also resulted in decreased levels of testosterone because of the abnormality of hypothalamic-pituitary-testicular axis. Third, it might be the diminished serum protein level in the composition of the PSA.


Factors affecting COVID-19 vaccine hesitancy among healthcare providers in 23 countries.
Several early COVID-19 studies aimed to assess the potential acceptance of a vaccine among healthcare providers, but relatively few studies of this population have been published since the vaccines became widely available. Vaccine safety, speed of development, and low perceived disease risk were commonly cited as factors for COVID-19 vaccine hesitancy among this group. In a secondary analysis based on a cross-sectional, structured survey, the authors aimed to assess the associations between self-reported vaccine hesitancy and a number of sociodemographic and COVID-19 vaccine perception factors using data from 3,295 healthcare providers (physicians, nurses, community health workers, other healthcare providers) in 23 countries. 494 (15.0%) of the participants reported vaccine hesitancy, of whom 132 (4.0%) would outright refuse to accept a COVID-19 vaccine. Physicians were the least hesitant. Vaccine hesitancy was more likely to occur among those with less than the median income and, to a lesser degree, younger age. Safety and risk concerns and lack of trust that vaccines would be equitably distributed were strongly associated with hesitancy, less so were concerns about the efficacy of COVID-19 vaccines. Findings suggest a need to address safety and risk concerns through tailored messaging, training, and/or incentive approaches among healthcare providers, as well as the need for international and national vaccination efforts to ensure equitable distribution.


Quantum curcumin mediated inhibition of gingipains and mixed-biofilm of Porphyromonas gingivalis causing chronic periodontitis.
Periodontitis is a biofilm-associated irreversible inflammation of the periodontal tissues. Reports suggest the role of Porphyromonas gingivalis specific Arg- and Lys-specific proteinases in the orchestration of the initiation and progression of periodontal diseases. These proteinases are precisely termed as gingipains R and K. Curcumin is an active polyphenol that is extracted from the rhizomes of Curcuma longa. However, the molecule curcumin owing to its high hydropathy index and poor stability has not been able to justify its role as frontline drug modality in the treatment of infectious and non-infectious diseases as claimed by several investigators. In the present study, at first, we synthesized and characterized quantum curcumin, and investigated its biocompatibility. This was subsequently followed by the evaluation of the role of quantum curcumin as an antimicrobial, anti-gingipains and antibiofilm agent against Porphyromonas gingivalis and select reference strains. We have successfully synthesized the quantum curcumin utilizing a top-down approach with the average size of 3.5 nm. Apart from its potent antimicrobial as well as antibiofilm properties, it also significantly inhibited the gingipains in a dose-dependent manner. At the minimal concentration of 17.826 μM, inhibition up to 98.7% and 89.4% was noted for gingipain R and K respectively. The data was also supported by the in silico docking experiments which revealed high exothermic enthalpies (-7.01 and -7.02 cal mol-1). Besides, the inhibition constant was found to be 7.24 μM and 7.1 μM against gingipains R and K respectively. The results suggest that quantum curcumin is a potential drug candidate which needs further clinical validation.


Man-biting species of Chrysops meigen, Culicoides latreille and Simulium latreille in Ethiopia, with discussion of their vector potentialities.
Human filariasis and its vectors are little known in Ethiopia. Wuchereia bancrofti is confined to the western lowlands and cannot be the aetiological agent of elephantiasis in the highlands. Onchocerca volvulus is widespread in the south-western highlands. Loa loa and Dipetalonema perstans are reported here for the first time and appear to be uncommon. Studies were conducted in 1973, mostly near Jimma in Kaffa Province, on potential vectors of all but the first of these parasites. Among Simuliidae, the only blackflies of apparent medical importance were S. woodi ethiopiense and a possibly new member of the S. damnosum complex. The former is less seasonal and much less numerous than the latter, but may be more widespread and important along smaller and higher streams. Onchocerca larvae were recovered from "damnosum", but not from the small number (46) of ethiopiense examined. In August, at the height of the rainy season, the biting-rate of ethiopiense at 1,710 m altitude on the Gilgil Ghibe river reached 9.5/man-hour at 10-1100 hours and about 12/man-hour at 14-1600 hours. At the same time and place, the attack of "damnosum" reached a midday climax of about 1,800/man-hour; this peak could be delayed or suppressed by rain. Another possibly anthropophilic blackfly, S. dentulosum, tended to become most common in December afer the rainy season had passed, but proved incompetent to bite man successfully. The only feasible loiasis vector found in Ethiopia was Chrysops streptobalius; however, this tabanid was not closely associated with man. Up to 34/man-day were caught in watermeadows by the Gojeb river (altitude 1,160 m) in October. Man-biting species of Ceratopogonidae in various parts of Ethiopia were Culicoides fulvithorax, C. grahamii, C. kingi and C. milnei. The first two of these were anthropophilic in lowlands, but apparently not so in highlands. C. milnei was extremely abundant biting man highlands. C. milnei was extremely abundant biting man and domestic animals both indoors and outdg cycle was irregular, usually displaying a succession of ill-define nocturnal peaks; sometimes it attacked in daylight. Up to 35,000 C. milnei per trap-night were caught in light traps. Most of the females entering light traps in a stable were already engorged with blood. It seemed very likely that C. milnei would prove to be of veterinary importance. No firm indication was obtained as to what may transmit D. perstans in Ethiopia.


High-dose computed tomography in the evaluation of low attenuation lesions in the neck.
Recent reports have established the clinical utility of computed tomography (CT) in the evaluation of jugular vein thrombosis. Other abnormalities of the soft tissues in the neck can mimic this condition. This study reviews the pertinent normal soft tissue and vascular anatomy of the neck and describes the use of high-dose CT in the evaluation of low attenuation lesions in this area. Various abnormalities are compared and contrasted, including cystic hygroma, neoplasm, abscess, and venous thrombosis.


Association of childhood obesity with female infertility in adulthood: a 25-year follow-up study.
To evaluate whether childhood obesity is associated with infertility in women's reproductive-aged life. Prospective longitudinal study. Not applicable. None. A total of 1,544 girls, aged 7-15 years in 1985, and who completed questionnaires at follow-up in 2004-2006 and/or 2009-2011. Infertility was defined as having difficulty conceiving (had tried for ≥12 months to become pregnant without succeeding) or having seen a doctor because of trouble becoming pregnant. At ages from 7-11 years, girls at both the lower and upper end of the body mass index (BMI) z score had increased risk of infertility. Compared with normal weight girls, those with obesity at ages 7-11 years were more likely in adulthood to report infertility (adjusted relative risk [aRR] = 2.94, 95% confidence interval [CI] 1.48-5.84), difficulty conceiving (aRR = 3.89, 95% CI 1.95-7.77), or having seen a doctor because of trouble becoming pregnant (aRR = 3.65, 95% CI 1.90-7.02) after adjusting for childhood age, follow-up length, highest parental education, and marital status. Childhood obesity before 12 years of age appears to increase the risk of female infertility in later life.


Evidence for decline in the incidence of cystic fibrosis: a 35-year observational study in Brittany, France.
Cystic fibrosis (CF) is an autosomal recessive disorder whose incidence has long been estimated as 1/2500 live births in Caucasians. Expanding implementation of newborn screening (NBS) programs now allows a better monitoring of the disease incidence, what is essential to make reliable predictions for disease management. This study assessed time trends in the birth incidence of CF over a long period (35 years: 1975-2009) in an area where CF is frequent (Brittany, France) and where NBS has been implemented for more than 20 years. This study enrolled CF patients born in Brittany between January 1st 1975 and December 31st 2009 (n = 483). Time trends in incidence were examined using Poisson regression and mainly expressed using the average percent change (APC). The average number of patients born each year declined from 18.6 in the late 1970's (period 1975-79) to 11.6 nowadays (period 2005-09). The corresponding incidence rates dropped from 1/1983 to 1/3268, which represented a decline close to 40% between these two periods (APC = -39.3%, 95% CI = -55.8% to -16.7%, p = 0.0020). A clear breakpoint in incidence rate was observed at the end of the 1980's (p < 0.0001). However, the incidence rate has remained quite stable since that time (annual APC = -1.0%, 95% CI = -3.0% to 1.1%, p = 0.3516). This study provides an accurate picture of the evolution of the incidence of a genetic disease over a long period and highlights how it is influenced by the health policies implemented. We observed a 40% drop in incidence in our area which seems consecutive to the availability of prenatal diagnosis.


Effect on the lipid parameters of an intervention to reduce weight in overweight and obese patients.
To assess the effect on lipid parameters most associated with excess weight (triglycerides [TG], cholesterol, and high density lipoprotein [HDL-C]) of an intervention to reduce weight in overweight and obese patients. A randomised, controlled, double blind clinical trial, with three groups, and a follow-up of 12 months. Patients included in the study were randomised into three intervention groups: Obesity motivational intervention group with previously trained nurse (G1), lower intensity consultation, non-motivational group, with digital platform support (G2), and a third group that received a recommendation to lose weight and usual follow-up (G3). The anthropometric variables measured were height, weight, and abdominal/waist circumference, and laboratory results, total cholesterol, TG and HDL cholesterol). The study include 176 patients, of whom 60 were randomised to G1, 61 to G2, and 59 to G3. All groups significantly decreased body weight at the end of the study, with a decrease in G1 (-5.6kg), followed by G2 (-4.3kg), and G3 (-1.7kg), with an overall mean loss of -3.9kg. There was a also significant decrease (P<.05) in total cholesterol and TG, and an increased HDL-C. These changes were more marked in the G1 group (the group that lost more weight). The clinical relevance indicators that were significant were: in the case of TG: G1/G3: relative risk: 1.42 (95% CI: 1.11-1.80); relative risk reduction: 41.7% (11.4-80.2); absolute risk reduction: 25% (9.2-40.8) and NNT: 5 (3-11). In the case of G1/G2 HDL-C: relative risk: 1.32 (1.07-1.63); relative risk reduction: 32.2% (7.4-62.6); absolute risk reduction: 21.1% (6.4-35.8) and NNT: 5 (3-16). Weight reduction is accompanied by favorable changes in the lipid parameters related to overweight and obesity, being more intense the greater the weight loss.


Novel strategies for clinical drug analysis with new column technology in liquid chromatography.
Clinical drug analysis has been the focus of much attention and controversy because of the increase in substance abuse testing of addicts, patients, employees and others, in addition to the rapidly growing fields of therapeutic drug monitoring and clinical toxicology. This review focuses on the latest methodological and technological advances in liquid chromatography (LC) as it is applied to clinical drug analysis. Based on the author's experience, key chromatographic parameters such as carbon load, functionalities and temperature are proposed for the separation of structurally similar metabolites and for resolving chromatographic interferences by other drugs and metabolites. Novel sample preparation for cyclosporine and gradient elution of its metabolites are reviewed, followed by an update on monitoring of 3'-azido-3'-deoxythymidine with emphasis on automated sample preparation. Various approaches of direct sample analysis are advocated for increased efficiency as a result of minimal sample preparation and potential advantages such as decreased exposure of personnel to infectious samples. An update of microbore LC indicates that 2-mm columns may be readily used for clinical paediatric and neonatal analysis without dedicated chromatographs. Potential applications of multidimensional-multimodal chromatography include analyses of a cocaine impurity, anticonvulsants, antidepressants, and five ingredients of a common cold medication.


WITHDRAWN: A comprehensive overview of online education - Impact on engineering students during COVID-19.
This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been withdrawn as part of the withdrawal of the Proceedings of the International Conference on Emerging Trends in Materials Science, Technology and Engineering (ICMSTE2K21). Subsequent to acceptance of these Proceedings papers by the responsible Guest Editors, Dr S. Sakthivel, Dr S. Karthikeyan and Dr I. A. Palani, several serious concerns arose regarding the integrity and veracity of the conference organisation and peer-review process. After a thorough investigation, the peer-review process was confirmed to fall beneath the high standards expected by Materials Today: Proceedings. The veracity of the conference also remains subject to serious doubt and therefore the entire Proceedings has been withdrawn in order to correct the scholarly record.


Activation of mitogen-activated protein (MAP) kinase by a MAP kinase-kinase.
Previously it has been shown that acute 12-O-tetradecanoylphorbol-13-acetate treatment of intact U937 cells results in activation of mitogen-activated protein (MAP) kinase and a MAP kinase activator. MAP kinase activator induces phosphorylation of MAP kinase on tyrosine and threonine residues, thereby activating MAP kinase. Here, experiments with the irreversible kinase inhibitor, 5'-p-fluorosulfonylbenzoyladenosine (FSBA), show that MAP kinase activator is in fact a MAP kinase-kinase. Treatment of MAP kinase activator with FSBA results in complete inactivation. This inactivation is prevented by a 10-fold excess of ATP. Inactivation of MAP kinase by FSBA does not affect the extent of threonine/tyrosine phosphorylation induced by MAP kinase-kinase.


Discontinuous shear thickening in Brownian suspensions by dynamic simulation.
Dynamic particle-scale numerical simulations are used to show that the shear thickening observed in dense colloidal, or Brownian, suspensions is of a similar nature to that observed in noncolloidal suspensions, i.e., a stress-induced transition from a flow of lubricated near-contacting particles to a flow of a frictionally contacting network of particles. Abrupt (or discontinuous) shear thickening is found to be a geometric rather than hydrodynamic phenomenon; it stems from the strong sensitivity of the jamming volume fraction to the nature of contact forces between suspended particles. The thickening obtained in a colloidal suspension of purely hard frictional spheres is qualitatively similar to experimental observations. However, the agreement cannot be made quantitative with only hydrodynamics, frictional contacts, and Brownian forces. Therefore, the role of a short-range repulsive potential mimicking the stabilization of actual suspensions on the thickening is studied. The effects of Brownian and repulsive forces on the onset stress can be combined in an additive manner. The simulations including Brownian and stabilizing forces show excellent agreement with experimental data for the viscosity η and the second normal stress difference N2.


Pepaxto: A New Peptide-Drug Conjugate for Heavily Pretreated Relapsed and Refractory Multiple Myeloma.
The objective of this article was to review existing data of melflufen (Pepaxto) as an additional treatment option for heavily pretreated relapsed and refractory multiple myeloma. A PubMed search was completed using the search terms melphalan flufenamide; melflufen; melflufen AND relapsed refractory multiple myeloma; melphalan flufenamide and relapsed refractory multiple myeloma between January 1, 2013, and October 18, 2021. Additional information was obtained from the National Institutes of Health Clinical Trial Registry, Federal Drug Administration (FDA) web updates, and Pepaxto prescribing information. Clinical trials including melflufen in relapsed refractory multiple myeloma and trials related to safety and clinical pharmacology were included. The findings of this review show melflufen in combination with dexamethasone can be used as a treatment option for patients with relapsed and refractory multiple myeloma who have previously received greater than 4 previous lines of therapy, and documented resistance to a proteosome inhibitor, an anti-CD38 monoclonal antibody, and an immunomodulator. Melflufen in combination with dexamethasone is a reasonable option for patients with relapsed and refractory multiple myeloma who have received at least 4 previous lines of therapy and considered ineligible for autologous stem cell transplant. Further clinical utilization in earlier lines of therapy is under review, pending the in-depth safety analysis by the FDA. The FDA approval of melflufen in combination with dexamethasone provides an additional therapy option for patients with heavily pretreated relapsed and refractory multiple myeloma.


Regio- and stereoselective synthesis of tetrasubstituted (E)-(2-chloro-2-fluoro-1-iodovinyl)dimethylphenylsilane and its desilylative sonogashira coupling.
Trihalo-substituted vinylsilane was readily synthesized in 77% yield and in an excellent regio- and stereoselective manner from in situ-generated fluorosilylacetylene, followed by the addition of I2 and NCS. The silane was committed to sequential Sonogashira coupling with various terminal acetylenes under mild conditions, affording desilylated chlorofluoro-enyne adducts in moderate to good yields.


Primary CNS lymphoma as a cause of Korsakoff syndrome.
Korsakoff syndrome presents with memory dysfunction with retrograde amnesia, anterograde amnesia, limited insight into dysfunction, and confabulation. The most common etiology of Korsakoff syndrome is thiamine deficiency secondary to alcoholism. There are limited case reports of structural lesions causing Korsakoff syndrome. A 46-year-old male with a long history of alcoholism presented with a history of confusion, amnesia, and confabulation with no localizing features on neurological examination. The patient showed no clinical change with intravenous thiamine. Computed tomography of the brain revealed a heterogenous, enhancing mass lesion centered within the third ventricle, with other lesions found throughout cortical and subcortical regions. The patient was given dexamethasone i.v. without noticeable clinical improvement but with marked radiological improvement with mass reduction. Stereotactic biopsy revealed a diagnosis of primary central nervous system (CNS) lymphoma. Most patients presenting with Korsakoff syndrome have thiamine deficiency; however, mass lesions can produce an identical clinical picture. This is the first case report of a patient with primary CNS lymphoma presenting as Korsakoff syndrome.


Factors affecting withdrawal and donation attrition in the brains for dementia research cohort.
To measure two forms of attrition in a cohort of volunteer brain donors: Withdrawal during life and non-donation at death. To test whether cognitive impairment independently predicts attrition. Attrition rates were calculated for all registered participants and for all brain donors who had completed a baseline and follow-up assessment of cognition, health, and lifestyle. Attrition reasons were described, and attrition rates were compared by gender, age group, and cognitive status. Multivariate logistic regression was used to identify the factors which independently predicted during life and at death. A total of 3276 brain donors registered and 2307 (70.4%) remained in the cohort. Attrition rate overall was 5.9% for withdrawal and 13.8% for donation. Family disagreement and the brain bank not being informed of participant death were the most common reasons for withdrawal and donation attrition. Withdrawal was associated with having cognitive impairment (OR 2.0 95% CI 1.1-3.5), increased age (OR 3.1 95% CI 1.4-6.9), and lower education (OR 1.8 95% CI 1.2-2.8). Participants exhibiting cognitive decline between assessments were more likely to withdraw (OR 4.9 95% CI 1.7-13.6). Participants living alone were almost twice as likely to die without donating (OR 1.9 95% CI 1.1-3.3). Attrition rates were relatively low, and consistent with other studies cognitive impairment, increased age, and less education predicted study withdrawal. Deaths of participants living alone were less likely to result in donation. Tailored, regular retention practices aimed at resolving family disagreement regarding donation decisions are required.


Octyl cyanoacrylate skin adhesive with or without subcuticular suture for skin closure after implantable venous port placement for oncology patients: a propensity-score matching analysis.
To compare peri-operative outcomes of skin closure with octyl cyanoacrylate (OCA) skin adhesive (Dermabond) with or without subcuticular sutures after deep dermal suturing for implantable venous port placement closure. Seven hundred and ninety-two single-lumen implantable venous port insertions for chemotherapy were reviewed from September 2019 to March 2021 in a retrospective single-centre study. Propensity-score matching by a 1:1 nearest neighbour algorithm was conducted to control for confounding baseline differences. Distances were determined by logistic regression. Propensity-score matching was performed based on the following variables: age at procedure, gender, race, operator's seniority, use of anchoring polypropylene suture (PROLENE), port model, and volume of intra-operative local analgesia. The primary outcome was wound dehiscence at the first follow-up (∼1 week). The 792 port insertions were conducted in 302 males (38.1%), median age 63 years (IQR: 54-69). Of the 656 wounds closed with subcuticular sutures and skin adhesive, 136 were matched in a 1:1 fashion against procedures closed without a subcuticular suture. No significant differences were demonstrated in pain scores, bleeding, swelling, bruising, fever, wound dehiscence, and discharge at postoperative day 1 (POD1) and at first follow-up between the groups (all p>0.05). Of note, no significant differences in wound dehiscence at first follow-up was found in both unmatched (p=0.133) and matched cohorts (McNemar-Bowker's χ2 = 1.167, p=0.761). These findings suggest that the omission of subcuticular sutures during implantable venous port closure may not compromise peri-operative outcomes when OCA skin adhesives were used.


Structure-guided pharmacophore based virtual screening, docking, and molecular dynamics to discover repurposed drugs as novel inhibitors against endoribonuclease Nsp15 of SARS-CoV-2.
COVID-19 (Corona Virus Disease of 2019) caused by the novel 'Severe Acute Respiratory Syndrome Coronavirus-2' (SARS-CoV-2) has wreaked havoc on human health and the global economy. As a result, for new medication development, it's critical to investigate possible therapeutic targets against the novel virus. 'Non-structural protein 15' (Nsp15) endonuclease is one of the crucial targets which helps in the replication of virus and virulence in the host immune system. Here, in the current study, we developed the structure-based pharmacophore model based on Nsp15-UMP interactions and virtually screened several databases against the selected model. To validate the screening process, we docked the top hits obtained after secondary filtering (Lipinski's rule of five, ADMET & Topkat) followed by 100 ns molecular dynamics (MD) simulations. Next, to revalidate the MD simulation studies, we have calculated the binding free energy of each complex using the MM-PBSA procedure. The discovered repurposed drugs can aid the rational design of novel inhibitors for Nsp15 of the SARS-CoV-2 enzyme and may be considered for immediate drug development.


A repertoire of alginate lyases in the alginate polysaccharide utilization loci of marine bacterium Wenyingzhuangia fucanilytica: biochemical properties and action pattern.
Alginate lyases are important tools for alginate biodegradation and oligosaccharide production, which have great potential in food and biofuel fields. The alginate polysaccharide utilization loci (PUL) typically encode a series of alginate lyases with a synergistic action pattern. Exploring valuable alginate lyases and revealing the synergistic effect of enzymes in the PUL is of great significance. An alginate PUL was discovered from the marine bacterium Wenyingzhuangia fucanilytica CZ1127T , and a repertoire of alginate lyases within it was cloned, expressed and characterized. The four alginate lyases in PUL demonstrated similar optimal reaction conditions: maximum enzyme activity at 35-50 °C and pH 8.0-9.0. The results of action pattern indicated that they were two PL7 endolytic bifunctional enzymes (Aly7A and Aly7B), a PL6 exolytic bifunctional enzyme (Aly6A) and a PL17 exolytic M-specific enzyme (Aly17A). Ultra-performance liquid chromatography-mass spectrometry was employed to reveal the synergistic effect of the four enzymes. The end products of Aly7A were further degraded by Aly7B and eventually generated oligosaccharides, from disaccharide to heptasaccharide. The oligosaccharide products were completely degraded to monosaccharides by Aly6A, but it was unable to directly degrade alginate. Aly17A could also produce monosaccharides by cleaving the M-blocks of oligosaccharide products, as well as the M-blocks of polysaccharides. The combination of these enzymes resulted in the complete degradation of alginate to monosaccharides. A new alginate PUL was mined and four novel alginate lyases in the PUL were expressed and characterized. The four cooperative alginate lyases provide novel tools for alginate degradation and biological fermentation. © 2023 Society of Chemical Industry.


Progress in chemotherapy of non-small cell lung cancer.
We reviewed the results in the literature on chemotherapy with cisplatin and/or other new agents such as etoposide and vindesine in the treatment of non-small cell lung cancer. Associations of cisplatin with vindesine or etoposide have been overall superior to combinations of older cytostatic agents. These combinations result in an average of 30-40% objective response rate with 5% complete responses. High doses of cisplatin seem to be associated with optimal results. Vinblastine, vincristine, bleomycin, methyl-GAG and dihydrogalactitol appear to be promising in combination with cisplatin.


Cloning and soluble expression of mature α-luffin from Luffa cylindrica in E. coli using SUMO fusion protein.
α-Lufin, found in Luaf cylindrica seeds, is a type I ribosome inactivating proteins. Cytotoxic effects make it an appropriate candidate for the construction of immunotoxins and conjugates. Because of limited natural resources, recombinant technology is the best approach to achieve large-scale production of plant-based proteins. In the present study, α-lufin protein was expressed in E. coli and the effects of different temperature conditions, SUMO fusion tag, and cultivation strategies on total expression and solubility were investigated. Protein expression was evaluated at different intervals (0, 4, 6, 8, 24 h) postinduction. Our results showed that EnBase had higher eficiency than LB, and maximum solubility and total protein expression were achieved 24 h after induction at 30 °C and 25 °C, respectively. It was shown that SUMO tag is an effective strategy to improve protein solubility.


[Injuries and their causes in bicycle accidents].
From April to September 1984 456 bicycle accidents were registered (73% adults, 27% children) and classified according to type and severity of injury and cause of accident. Of 594 injuries those of the upper extremities were predominant followed by mostly severe head injuries. The commonest injury was the fracture of clavicle and thereafter fractures of the radial head and distal radial fractures in children. 59% of accidents occurred without involvement of another person. 58% of accidents were caused by the bicycle riders themselves.


Isocitrate dehydrogenase 3b is required for spermiogenesis but dispensable for retinal viability.
Isocitrate dehydrogenase 3 (IDH3) is a key enzyme in the mitochondrial tricarboxylic acid (TCA) cycle, which catalyzes the decarboxylation of isocitrate into α-ketoglutarate and concurrently converts NAD+ into NADH. Dysfunction of IDH3B, the β subunit of IDH3, has been previously correlated with retinal degeneration and male infertility in humans, but tissue-specific effects of IDH3 dysfunction are unclear. Here, we generated Idh3b-KO mice and found that IDH3B is essential for IDH3 activity in multiple tissues. We determined that loss of Idh3b in mice causes substantial accumulation of isocitrate and its precursors in the TCA cycle, particularly in the testes, whereas the levels of the downstream metabolites remain unchanged or slightly increased. However, the Idh3b-KO mice did not fully recapitulate the defects observed in humans. Global deletion of Idh3b only causes male infertility but not retinal degeneration in mice. Our investigation showed that loss of Idh3b causes an energetic deficit and disrupts the biogenesis of acrosome and flagellum, resulting in spermiogenesis arrestment in sperm cells. Together, we demonstrate that IDH3B controls its substrate levels in the TCA cycle, and it is required for sperm mitochondrial metabolism and spermiogenesis, highlighting the importance of the tissue-specific function of the ubiquitous TCA cycle.


An Examination of the Effectiveness of Smoking Cessation Treatment Interventions for Individuals with Severe Mental Illness: A Pilot Randomized Controlled Trial.
To evaluate the effectiveness of two different smoking cessation interventions for individuals with severe mental illness. Study participants (N = 61) randomly assigned to the SC-R group (n = 29) were offered 24 weeks of no cost Nicotine Replacement Treatment (NRT); participants assigned to the SC + group (n = 32) were offered 24 weeks of no cost NRT plus two initial individual counselling sessions of motivational interviewing and weekly psychosocial group support for 24 weeks. At 6 months the smoking cessation outcome was 7% for the SC-R group and 14% for the SC + group, but there was no statistically significant difference between the groups. Both groups showed a significant decrease in the number of cigarettes smoked per day and significant improvement in physical health functioning. Clients with severe mental illness, high prevalence of co-occurring substance use and experience of homelessness, are both interested and able to quit smoking and reduce cigarette use.


Somatosensory cerebral potentials evoked by stimulation of the lumbo-sacral spinal cord in normal subjects and in patients with conus medullaris and cauda equina lesions.
Somatosensory cerebral evoked potentials were recorded by intrathecal stimulation of the lumbo-sacral cord and roots in 16 normal subjects and patients having cauda/conus injury (group A, 15 cases), compressive lesions of cauda equina (group B, 13 cases) and lesions of both types covering the lumbar cord (group C, 24 cases). The shape of the intrathecally evoked cerebral potential (IECP) was basically the same as that obtained by posterior tibial nerve stimulation from 12 normal subjects except that the early components were 10-15 msec shorter in latency in the former potential, with an average of 12 msec. IECPs were easily recorded in groups A and B, but a significant delay was found in both groups, especially group A. It was difficult to obtain the IECP in group C, When it could be recorded the latency increase was apparent. These findings were explained on the basis of degeneration of the ascending spinal nerve fibers proximal to the lesion site.


Integrated parasite management with special reference to gastro-intestinal nematodes.
Domestic animals are susceptible to a large number of parasitic diseases, which lead to severe economic losses to livestock industry. So, it is necessary to control parasitic infections in these animals. Control of these helminths is undertaken mostly by anthelmintics, but because of their widespread use there is development of resistance across the globe. However, total dependence on a single method of control has proved to be non-sustainable and cost ineffective in the long term. A combination of treatment and management is necessary to control parasitism so that it will not cause further economic losses to producer as well as to livestock industry. To become practically and ecologically sustainable, parasitic control schemes need to be based on integrated parasite management.


Predator migration in response to prey density: what are the consequences?
A predator-prey metapopulation model with two identical patches and only migration of the predator is investigated. Local predator-prey interaction is described by the so-called Rosenzweig-MacArthur model, while the migration term of the predator is put in a nonlinear form, which is derived by extending the Holling time budget argument to migration. In particular, a dimensionless parameter theta is introduced to quantify the migration tendency of predators while they are handling their prey, which gives rise to a family of models connecting two extremes: predators have no inclination to migrate while handling prey (theta = 0) and standard diffusion (theta = 1). Various aspects of the model, including changes in the number and the stability of equilibria and limit cycles, are investigated. We then focus on the key question: "Does spatial structure lead to a substantial damping of the violent oscillations exhibited by many predator-prey models?". It is known that the answer is "yes" if one adopts standard diffusion (theta = 1). However, we present substantial evidence that the answer is "no" if one takes theta = 0. We conclude that the migration submodel is an important constituent of a spatial predator-prey model and that the issue deserves scrutiny, both experimentally and theoretically.


Impact of cerebral palsy on health-related physical fitness in adults: systematic review.
To conduct a systematic review of the impact of cerebral palsy (CP) on the level of health-related physical fitness (body composition, cardiorespiratory endurance, flexibility, muscular endurance, and strength) in adults with CP compared with able-bodied adults. The Cochrane Library, MEDLINE, CINAHL, EMBASE, and PEDro were searched up to December 2010 for relevant comparative studies. Two reviewers independently applied the inclusion criteria (adults, comparative design, components of physical fitness) to select potential relevant studies. Two reviewers independently extracted the data and assessed the methodological quality. A consensus method was used to solve disagreements. Pooling data was not possible, but a best-evidence synthesis was conducted. Also, a description of the level of health-related physical fitness in CP was given (expressed as a percentage of able-bodied controls). Nine case-control studies were included (average age ± SD of subjects with CP, 21±3y): 3 investigated body composition; 5, cardiorespiratory endurance; 3, muscular strength; and 1, muscular endurance. Two of the studies investigated multiple fitness components. No studies on flexibility were found. Muscular strength (34%-60%), muscular endurance (27%-52%), and cardiorespiratory endurance (14%) showed significantly lower values in adults with CP compared with able-bodied controls. Studies on body composition reported conflicting results on the impact of CP. The results of this review point to a reduction in 3 components of health-related physical fitness in young adults with CP compared with controls: muscular strength, muscular endurance, and cardiorespiratory endurance. However, the level of evidence varies from moderate (muscular strength) to limited (muscular endurance and cardiorespiratory endurance). Additional studies of high methodological quality are recommended before firm conclusions can be made.


Detection and quantification of intracerebral and intraventricular hemorrhage from computed tomography images with adaptive thresholding and case-based reasoning.
Hemorrhage within the brain space (HWBS) involves the brain parenchyma and ventricle systems, and is associated with high morbidity and mortality. Computed tomography (CT) head scans are the recommended modality for diagnosis and treatment for HWBS. However, HWBS detection may be difficult when the hemorrhage is inconspicuous, while quantification is hard as hemorrhage can have very variable intensity that overlaps with normal brain tissue. An algorithm is proposed to detect and quantify HWBS. Adaptive thresholding and case-based reasoning (CBR) were applied to HWBS in four steps: preprocessing to extract the brain, adaptive thresholding based on local contrast with varied window sizes to derive candidate HWBS regions, case representation to represent each candidate HWBS region by parameters on context as well as intensity and geometrical characteristics, and classification of HWBS by taking each candidate HWBS region as a case and applying CBR. Additionally, case base indexing and weights optimization were used to increase retrieval speed and improve performances. Refinement of each recognized HWBS was performed for quantifying HWBS. Validation on 426 clinical CT data indicates that the proposed algorithm achieved a detection rate of 94.4 % and recall of 79.2 % for detecting HWBS regions. Visually, the HWBS regions calculated from adaptive thresholding plus refinement agreed well with expert delineation. For 10 representative data with small to large hemorrhage, the algorithm quantitatively yielded a segmentation accuracy of [Formula: see text]. Case base indexing increased the retrieval speed by 41.1 times at the expense of decreasing detection rate of 0.5 % and recall of 2.6 %. Genetic algorithm optimization enhanced the detection rate and recall to, respectively, 94.9 and 83.5 %. We developed and tested an algorithm that combined adaptive thresholding and CBR for detecting and quantifying HWBS. Experiments showed that adaptive thresholding could provide suitable candidates, while CBR was able to identify HWBS regions. The proposed method has potential as a new tool for accurately detecting and quantifying HWBS.


The value of adnexal sonographic findings in the diagnosis of ectopic pregnancy.
A prospective study of 383 patients with suspected ectopic pregnancy was carried out at Yale-New Haven Hospital to determine the value of adnexal sonographic findings in the diagnosis of ectopic pregnancy. In patients with adnexal sonographic results and human chorionic gonadotropin titers less than 6000 mIU/ml (n = 220), the presence of a noncystic mass had a positive predictive value of 83%, and the presence of a cystic mass had a positive predictive value of 35%. The combination of a noncystic mass and fluid in the cul-de-sac (found in 22% of all patients with ectopic gestations) was the best predictor of an ectopic pregnancy with a 94% positive predictive value. It is suggested that the demonstration of a non-cystic mass, alone or in the presence of fluid in the cul-de-sac, be used as an indication for diagnostic laparoscopy.


The circular RNA-NRIP1 plays oncogenic roles by targeting microRNA-505 in the renal carcinoma cell lines.
We explored the roles and regulatory mechanisms of the circular RNA (circRNA) nuclear receptor-interacting protein 1 (NRIP1; circNRIP1) in ACHN and CAKI-1 cells. ACHN and CAKI-1 cells were transfected with small-interfering-circNRIP1 (si-circNRIP1) and microRNA-505 (miR-505) inhibitor or the corresponding controls. Cell viability was detected with the Cell Counting Kit-8. The protein expression levels of Bcl-2, Bax, cleaved-caspase-3, matrix metalloproteinase (MMP)-2, MMP-9, adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), protein kinase B (AKT), phosphatidylinositol 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) were individually determined via Western blot. Quantitative reverse transcription polymerase chain reaction was used to examine the expressions of circNRIP1 and miR-505 both in tumor cells and tissues. The apoptotic rate, the colony numbers, and the migration rate were separately determined by the Annexin V-fluorescein isothiocyanate/propidium iodide and flow cytometer, colony formation assay, and migration assay. We found that circNRIP1 was overexpressed in tumor tissue but miR-505 was overproduced. Silencing circZNF292 induced inhibition of cell viability, colony formation, and migration, as well as the activity of AMPK and PI3K/AKT/mTOR cascades but enhancement of apoptosis. si-circNRIP1 stimulated the upregulation of miR-505, whose silence abolished the effects of si-circNRIP1 on these elements mentioned above. In conclusion, the circNRIP1 played oncogenic roles in the ACHN and the CAKI-1 cell lines by targeting miR-505 via stimulating AMPK and PI3K/AKT/mTOR cascades.


The involvement of the bridging imidazolate in the catalytic mechanism of action of bovine superoxide dismutase.
The pulse-radiolysis method has been used to study the catalytic mechanism of O2 leads to dismutation by the Co(II)-substituted bovine erythrocuprein (superoxide dismutase, EC 220.127.116.11). Catalysis is accompanied by spectral changes that may be interpreted in terms of rapid protonation and deprotonation of the Cu-facing nitrogen atom of the imidazolate that bridges the Cu(II) and the Co(II) [or Zn(II)] in the oxidized enzyme. This rapid change permits the possibility that the imidazole is a proton donor in the catalytic reduction of O2 leads to.


Uptake and degradation of EDTA by Escherichia coli.
It was found that Escherichia coli exhibited a growth by utilization of Fe(III)EDTA as a sole nitrogen source. No significant growth was detected when Fe(III)EDTA was replaced by EDTA complexes with other metal ions such as Ca(2+), Co(2+), Cu(2+), Mg(2+), Mn(2+), and Zn(2+). When EDTA uptake was measured in the presence of various ions, it was remarkable only when Fe(3+) was present. The cell extract of E. coli exhibited a significant degradation of EDTA only in the presence of Fe(3+). It is likely that the capability of E. coli for the growth by utilization of Fe(III)EDTA results from the Fe(3+)-dependent uptake and degradation of EDTA.


Individually tailored treatment targeting motor behavior, cognition, and disability: 2 experimental single-case studies of patients with recurrent and persistent musculoskeletal pain in primary health care.
This article introduces an individually tailored intervention targeting motor behavior, cognition, and disability in patients managed by physical therapists in primary health care. Effects on self-rated disability, pain intensity, and pain control are described. Two women with recurrent or persistent disabling musculoskeletal pain were selected. Two experimental single-subject A(1)-B-C-A(2) studies with multiple baselines across situations were used. Principal outcome data were collected daily with patient-specific continuous measures for 3 weeks before intervention, continuously during intervention, and for 2 weeks during each of the 1-, 4-, 6-, and 12-month follow-up examinations. Disability and pain intensity decreased, and pain control increased in both subjects. The results were maintained at the follow-up examinations. Positive outcomes of the intervention were reported from 2 subjects with recurrent and persistent disabling pain. Procedures for systematic tailoring of treatment to behavioral goals and individual patient characteristics are available as a result of the successful application. The results need to be replicated in future clinical controlled group studies.


River network rearrangements promote speciation in lowland Amazonian birds.
Large Amazonian rivers impede dispersal for many species, but lowland river networks frequently rearrange, thereby altering the location and effectiveness of river barriers through time. These rearrangements may promote biotic diversification by facilitating episodic allopatry and secondary contact among populations. We sequenced genome-wide markers to evaluate the histories of divergence and introgression in six Amazonian avian species complexes. We first tested the assumption that rivers are barriers for these taxa and found that even relatively small rivers facilitate divergence. We then tested whether species diverged with gene flow and recovered reticulate histories for all species, including one potential case of hybrid speciation. Our results support the hypothesis that river rearrangements promote speciation and reveal that many rainforest taxa are micro-endemic, unrecognized, and thus threatened with imminent extinction. We propose that Amazonian hyper-diversity originates partly from fine-scale barrier displacement processes-including river dynamics-which allow small populations to differentiate and disperse into secondary contact.


[Diagnosis and management of acute pulmonary embolism. ESC guidelines 2014].
Acute pulmonary embolism (PE) still represents a challenge regarding a rapid diagnosis and a risk-adapted therapy. In the 2014 guidelines of the European Society of Cardiology (ESC) on the diagnosis and management of acute PE, several new recommendations have been issued based on new study data. Some established scores for risk stratification were developed further and there is now good evidence for the use of age-adjusted D-dimer cut-off levels. For the risk stratification in patients without clinical features of shock, the utilization of the pulmonary embolism severity index (PESI) and simplified PESI (sPESI) scores is recommended. In patients with intermediate risk, right ventricular morphology and function can be evaluated by computer tomography or echocardiography and biomarkers facilitate further risk stratification. For the treatment of patients with venous thromboembolism with or without PE, the non-vitamin K-dependent oral anticoagulants (NOACs) are a safe alternative to the standard anticoagulation regimen with heparin and vitamin K antagonists. Systemic thrombolytic therapy should be restricted to patients with high risk or intermediate high risk with hemodynamic instability. Finally, new recommendations for the diagnosis and therapy of patients with chronic thromboembolic pulmonary hypertension (CTEPH), with cancer or during pregnancy are given.


Positron emission tomography enhancing tumor thrombus in patient with renal cell carcinoma.
A 65-year-old man underwent computed tomography (CT) of the abdomen during evaluation for anemia which showed a 10 cm right renal mass and inferior vena cava (IVC) thrombus. Positron emission tomography (PET)/CT revealed uptake of flurorodeoxyglucose (FDG) within only the tumor mass and thrombus. Right radical nephrectomy and IVC thrombectomy with IVC patch graft reconstruction were performed. Final pathology showed pT3bNxMx renal cell carcinoma (RCC) with IVC thrombus composed of poorly differentiated RCC. There is no evidence of recurrence at one year follow-up. We discuss the role of PET in RCC.


Bilateral cataract, crash risk, driving performance, and self-regulation practices among older drivers.
This comprehensive literature review summarizes published studies examining cataract and cataract surgery and driving outcomes to identify gaps in the literature that require further research. Six electronic databases were searched for articles published up to and including March 2015. Articles were reviewed if they included older drivers with cataract or drivers who had cataract surgery and at least 1 of the following driving outcomes: crash risk, driving self-regulation practices, and driving performance. There was consistent evidence that cataract negatively affects driving and that cataract surgery is beneficial to driving outcomes. Future research should examine the separate effects of first- and second-eye cataract surgery on crash risk, driving self-regulation, and driving performance. It should also determine how visual measures relate to driving performance among cataract patients so those most at risk for driving difficulties can be identified, advised, and possibly prioritized for surgery. No author has a financial or proprietary interest in any material or method mentioned.


Guizhi-Shaoyao-Zhimu decoction attenuates rheumatoid arthritis partially by reversing inflammation-immune system imbalance.
Guizhi-Shaoyao-Zhimu decoction (GSZD) has been extensively used for rheumatoid arthritis (RA) therapy. Marked therapeutic efficacy of GSZD acting on RA has been demonstrated in several long-term clinical trials without any significant side effects. However, its pharmacological mechanisms remain unclear due to a lack of appropriate scientific methodology. GSZD's mechanisms of action were investigated using an integrative approach that combined drug target prediction, network analysis, and experimental validation. A total of 77 putative targets were identified for 165 assessed chemical components of GSZD. After calculating the topological features of the nodes and edges in the created drug-target network, we identified a candidate GSZD-targeted signal axis that contained interactions between two putative GSZD targets [histone deacetylase 1 (HDAC1) and heat shock protein 90 kDa alpha, class A member 1 (HSP90AA1)] and three known RA-related targets [NFKB2; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB); and tumor necrosis factor-alpha (TNF-α)]. This signal axis could connect different functional modules that are significantly associated with various RA-related signaling pathways, including T/B cell receptor, Toll-like receptor, NF-kappa B and TNF pathways, as well as osteoclast differentiation. Furthermore, the therapeutic effects and putative molecular mechanisms of GSZD's actions on RA were experimentally validated in vitro and in vivo. GSZD may partially attenuate RA by reversing inflammation-immune system imbalance and regulating the HDAC1-HSP90AA1-NFKB2-IKBKB-TNF-α signaling axis.


Immunopotentiating properties of chimeric OprF-OprI-PopB protein against Pseudomonas aeruginosa PAO1 in the infected burned rat model.
Pseudomonas aeruginosa, as an opportunistic pathogen, is known to cause nosocomial infections among patients suffering from burn injuries and also cystic fibrosis patients. The objective of our research was to develop a novel vaccine against P. aeruginosa. A recombinant P. aeruginosa subunit vaccine based on the outer membrane proteins, including the OprF-OprI region and its major protein in the type III secretion system, PopB (called FIB protein) was formulated. To induce a robust immune response, our preferred regions were conjugated to a carrier protein, GMCSF (Granulocyte-macrophage colony-stimulating factor). FIB protein's immunogenicity with and without adjuvant was evaluated in vaccinated rats and also burned rat models, which were subcutaneously challenged by the PAO1 strain of P. aeruginosa. Antibody levels were increased in sera of rats in this study. Assessment of the resident memory CD4+ T cells in splenocytes from vaccinated rats demonstrated that the FIB conjugated with GMCSF could cause higher responses in comparison with other groups. Moreover, immunization with the FIB plus adjuvant protein could improve interferon-gamma (IFN-γ) production, interleukin 17A (IL-17A), and IL-4, contributing to elicit humoral and cellular immune responses and decreased post-infection bacterial loads after PA challenge, pathology, and inflammatory cell infiltration. These observations demonstrated that FIB conjugated with GMCSF can be a putative vaccine candidate against P. aeruginosa in burnt rat models.


Overweight and obesity in deltaF508 homozygous cystic fibrosis.
Overweight (9%) and obesity (1%) in patients with cystic fibrosis homozygous for the deltaF508 mutation (CFdeltaF508) were non-trivial. Children with CFdeltaF508, in contrast to the general population, showed a positive association between body mass index and lung function for all body mass index z-scores.


Rat steroid 5 alpha-reductase kinetic characteristics: extreme pH-dependency of the type II isozyme in prostate and epididymis homogenates.
Reevaluating the assay for rat steroid 5 alpha-reductase isozymes in prostate and epididymis homogenates we encountered an extreme pH-dependency of the type II isozyme. The time-course of the metabolism of testosterone (T) to 17 beta-hydroxy-5 alpha-androstan-3-one (DHT) at acidic pH shows an initial burst when the homogenate is not brought to pH before the start of the incubation. Therefore, the rat type II 5 alpha-reductase isozyme does not follow Michaelian law under these conditions making a single time point measurement invalid. Assessing the pH-optimum of 5 alpha-reduction in both rat prostate and epididymis homogenates we found a strong substrate dependency: at high substrate concentrations a pH-optimum for the type II isozyme of pH 5.0 was found, whereas at lower concentrations pH 5.5 is optimal. Establishing Vmax (maximum velocities) and Km (affinity constants) for the 5 alpha-reduction of T at pH 4.5-8.0, the efficiency optimum Vmax/Km appeared to be pH 5.5 in both prostate and epididymis homogenates. Specifically at acidic pH these kinetic characteristics of the type II isozyme vary many-fold. Discrepancies in literature concerning 5 alpha-reductase characteristics can, at least in part, be attributed to the choice of optimal pH, or to pH shifts during the assay.


Patient safety in rehabilitation medicine: traumatic brain injury.
This article describes patient safety after traumatic brain injury (TBI). Patient safety in rehabilitation after TBI is important. Thorough assessment on initial evaluation, vigilance for medical and procedural errors, appropriate communication between medical professionals, and evaluation of systems-based practices increases patient safety. It is the responsibility of the rehabilitation treatment team to ensure that appropriate measures are taken to reduce risk of adverse events. This article is intended to promote discussion of patient safety after TBI within rehabilitation teams and to help improve outcomes throughout the spectrum of recovery.


Connective tissue disease manifested as multiple myeloma.
A diagnosis of Sjögren's syndrome or rheumatoid arthritis was made in five women in whom multiple myeloma was first suspected. All had mild symptoms of sicca or arthritis, positive tests for rheumatoid factor or antinuclear antibody, and markedly increased IgG immunoglobulins. A connective tissue disorder may produce the characteristic electrophoretic pattern of multiple myeloma.


Doing the counter-regulation shuffle: The importance of flexibility and hunger for predicting food consumption following a preload.
This study utilised the preload paradigm to evaluate whether trait-like dieting attitudes and behaviours (dietary restraint and flexibility in dieting rules) and context-specific factors (negative mood and hunger) predict food consumption among male and female participants. Following a high calorie preload, 79 participants aged 18-40 completed a deceptive taste test in which they were encouraged to eat as much of the taste test foods as desired, and this ad libitum intake was measured. Although each predictor (except negative mood) predicted consumption when tested individually, regression analyses revealed that dieting flexibility and current hunger were the strongest unique predictors of intake. Mood failed to directly predict food consumption, nor did it moderate the relationship between restraint and food intake. Collectively, findings suggest that emphasis on dietary restraint in preload studies may be misplaced, as other proximal and stable factors may better predict food consumption.


The RNA Binding Protein HuR Promotes Neuronal Apoptosis in Rats with Spinal Cord Injury via the HDAC1/RAD21 Axis.
The current research aims to study the regulation of the RNA binding protein HuR on neuronal apoptosis during spinal cord injury (SCI) and its underlying mechanism. SCI rat models were injected with HuR shRNA and/or pcDNA3.1-RAD21, followed by the evaluation of motor function, the degree of SCI, the expression of HuR and RAD21, and neuronal-like apoptosis. The co-localization of HuR-RAD21, RAD21-NeuN, and NeuN-cleaved caspase 3 was measured by immunofluorescence. Additionally, targeting relationships among HuR, HDAC1, and RAD21 were verified by chromatin immunoprecipitation and RNA immunoprecipitation. After transfection, apoptosis of PC12 cells was tested by flow cytometry. Results showed that silencing HuR or up-regulating RAD21 could alleviate SCI and reduce neuronal apoptosis. HuR could combine HDAC1 mRNA, and HDAC1 combined the promoter of RAD21. Further experiments revealed that HuR enhanced HDAC1 expression and reduced RAD21 promoter region acetylation. Overexpression of RAD21 reversed the enhancement in apoptosis of PC12 cells caused by overexpression of HuR. The injection of HuR shRNA in tail vein of SCI rats increased basso, beattie, and bresnahan score, relieved SCI, reduced HuR and HDAC1 expression, elevated RAD21 expression, and decreased neuronal-like apoptosis. However, this result was reversed by co-injection of pcDNA3.1-HDAC1. In conclusion, down-regulation of HuR alleviated SCI and neuronal apoptosis in rats by suppressing HDAC1 expression and promoting RAD21 expression.


Antemortem diagnosis of nonbacterial thrombotic endocarditis in a patient with previously resected pancreatic adenocarcinoma: a case report.
Nonbacterial thrombotic endocarditis (NBTE) is a rare manifestation of a number of systemic diseases, which include advanced malignancy and hypercoagulable states. We present a 67-year-old woman who had presented with chest pain and heart failure. Eight years ago, she had a successful Whipple resection for pancreatic adenocarcinoma. Echocardiography revealed mitral valve vegetations with negative blood cultures. She had multiple infarcts in the kidney, spleen, and brain. She was found to have a mass in the left 8th rib, consistent with metastatic pancreatic adenocarcinoma on biopsy. Ultimately, a diagnosis of NBTE was made after excluding other causes for her presentation. Because of her general poor condition, she expressed the wish for palliative care and later died 28 days after presentation. This case illustrates the possibility of NBTE in patients successfully treated for pancreatic adenocarcinoma and highlights the consideration of this relatively rare differential in patients with a previously treated malignancy presenting with heart failure.


Effects of 25 pharmaceutical compounds to Lemna gibba using a seven-day static-renewal test.
Antibiotics are known to have antichloroplastic properties, but their effects on aquatic higher plants are virtually unknown. In order to address this issue, 25 pharmaceuticals, including 22 antibiotics, were assessed for phytotoxicity to the aquatic higher plant Lemna gibba. A 7-d static-renewal test was used, and plants were treated with 0, 10, 30, 100, 300, and 1,000 microg/L of pharmaceutical-containing growth media. Phytotoxicity was assessed using multiple growth and biochemical endpoints. Effective concentration (EC)50, EC25, and EC10 values as well as tests for significant differences between treatments and controls lowest-observed-effect concentration (LOECs) were calculated for each endpoint. Twelve different classes of antibiotics were assessed; however, only members of the fluoroquinolone, sulfonamide, and tetracycline classes of antibiotics displayed significant phytotoxicity. The most toxic members of each of these classes tested were lomefloxacin, sulfamethoxazole, and chlortetracycline, with wet weight EC25 values of 38, 37, and 114 microg/L, respectively. Injury symptoms were comparatively uniform and consistent among chemical classes while degree of phytotoxicity varied considerably. Both of these criteria varied markedly between classes. Wet mass was consistently the most sensitive endpoint above 100 microg/L; conversely, frond number was the most sensitive below 100 microg/L. Pigment endpoints were significantly less sensitive than growth endpoints.


Insulin-like growth factors (IGFs) and IGF-binding proteins in nephrotic syndrome children on glucocorticoid.
Growth failure is often seen in nephrotic children who fail to respond to glucocorticoid therapy or are glucocorticoid dependent. The underlying mechanism responsible for such growth defect remains poorly understood although long-term glucocorticoid use or nephrotic syndrome (NS) has been indicated to independently affect growth. Recent clinical evidence has suggested that changes in the serum levels of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) among these children. The loss of insulin-like growth factor-I (IGF-1) and IGFBP-3 found in nephrotic children may directly prompt growth defect and retardation. In addition, glucocorticoid is believed to be associated with overt elevation of serum IGF-I levels suggesting potential development of IGF resistance, one of the main factors responsible for persistent growth retardation. Growth hormone therapy has been shown to effectively reconcile this IGF resistance. The present review will discuss the complex relationship among IGF, IGFBPs, and glucocorticoid in children with NS.


Role of the wet-to-dry phase of cleansing in preparing the chronic wound bed for dressing application.
The wet-to-dry phase is a method of cleansing that acts as an alternative to rinsing prior to the application of a modern wound dressing. Debris, exudate and pathogens are removed from the wound, reducing itching and inflammation.


Needle-free powder lidocaine delivery system provides rapid effective analgesia for venipuncture or cannulation pain in children: randomized, double-blind Comparison of Venipuncture and Venous Cannulation Pain After Fast-Onset Needle-Free Powder Lidocaine or Placebo Treatment trial.
The Comparison of Venipuncture and Venous Cannulation Pain After Fast-Onset Needle-Free Powder Lidocaine or Placebo Treatment trial was a randomized, single-dose, double-blind, phase 3 study investigating whether a needle-free powder lidocaine delivery system (a sterile, prefilled, disposable system that delivers lidocaine powder into the epidermis) produces effective local analgesia within 1 to 3 minutes for venipuncture and peripheral venous cannulation procedures in children. Pediatric patients (3-18 years of age) were randomly assigned to treatment with the needle-free powder lidocaine delivery system (0.5 mg of lidocaine and 21 +/- 1 bar of pressure; n = 292) or a sham placebo system (n = 287) at the antecubital fossa or the back of the hand 1 to 3 minutes before venipuncture or cannulation. All patients rated the administration comfort of the needle-free systems and the pain of the subsequent venous access procedures with the Wong-Baker Faces Pain Rating Scale (from 0 to 5). Patients 8 to 18 years of age also provided self-reports with a visual analog scale, and parents provided observational visual analog scale scores for their child's venous access pain. Safety also was assessed. Immediately after administration, mean Wong-Baker Faces scale scores were 0.54 and 0.24 in the active system and sham placebo system groups, respectively. After venipuncture or cannulation, mean Wong-Baker Faces scale scores were 1.77 +/- 0.09 and 2.10 +/- 0.09 and mean visual analog scale scores were 22.62 +/- 1.80 mm and 31.97 +/- 1.82 mm in the active system and sham placebo system groups, respectively. Parents' assessments of their child's procedural pain were also lower in the active system group (21.35 +/- 1.43 vs 28.67 +/- 1.66). Treatment-related adverse events were generally mild and resolved without sequelae. Erythema and petechiae were more frequent in the active system group. The needle-free powder lidocaine delivery system was well tolerated and produced significant analgesia within 1 to 3 minutes.


Fly-ash as a low-cost material for isolation of phosphoproteins.
Metal oxide affinity chromatography (MOAC) is one of the most commonly used techniques for selective isolation phosphoproteins and phosphopeptides. This technique is capable of capturing the phosphorylated biomolecules through the affinity of the phosphoryl group for metal oxides/hydroxides. Fly-ash (FA), a by-product of coal-combustion power plants, is primarily composed of oxides of silicon and metals, among which iron and titanium. A number of studies have demonstrated the potential of these metal oxides for phosphoprotein and phosphopeptide enrichment. FA is annually produced over hundred million tons worldwide and generally considered as hazardous waste. It is thus of great importance to enhance its utilization. Here we present the first demonstration of the utility of FA as a low-cost MOAC material for the enrichment of phosphoproteins. With an FA-microcolumn, phosphoproteins can be successfully sequestered from other proteins. FA-microcolumns are shown to be simple, cheap and selective devices for phosphoprotein enrichment from a small volume of mixtures.


New Approaches for Immune Directed Treatment for Ovarian Cancer.
The immune system plays an active role in the pathogenesis of ovarian cancer (OC), as well as in the mechanisms of disease progression and overall survival (OS). Immunotherapy in gynecological cancers could help to revert immunosuppression and lymphocyte depletion due to prior treatments. Current immunotherapies for ovarian cancer, like all cancer immunotherapy, are based on either stimulating the immune system or reverting immune suppression. Several approaches have been used, including therapeutic vaccines, monoclonal antibodies; checkpoint inhibitors and adoptive T cell transfer. Most of these therapies are still in early-phase testing (phase I and II) for ovarian cancer, but the initial data in ovarian cancer and successful use in other types of cancers suggests some of these approaches may ultimately prove useful for ovarian cancer as well. Ovarian cancer vaccines have shown only a modest benefit in ovarian cancer when used as monotherapy, but these agents may be able to enhance antitumor activity when combined with chemotherapy, checkpoint inhibitors, or other immunotherapies. Monoclonal antibodies have been explored in ovarian cancer but despite encouraging phase II data, randomized studies failed to demonstrate significant clinical benefit. Check point inhibitors have promising activity in several solid tumors and have demonstrated a favorable toxicity profile. Data from early clinical trials utilizing PD1 and PD-L1 inhibitors showed encouraging results. Ongoing clinical trials are evaluating the role of check point inhibitors in combination with chemotherapy. Adoptive T cell transfer involves the infusion of ex vivo activated and expanded tumor specific T cells, using various sources and types of T cells. While this approach has been explored in several hematologic malignancies, it constitutes early research in ovarian cancer. Immunotherapy remains investigational in ovarian cancer and the benefit of this approach in improving progression-free survival (PFS) or OS is unknown. Previous clinical trials have not selected patients based on biomarkers and this may explain the negative results. We expect to discover that tumor response will relate to the patient's immune features and specific tumor characteristics. We are only beginning to realize the potential of immunotherapy for ovarian cancer patients, and one goal of future clinical trials will be to identify subsets of patient based on histologic, molecular, and immune characteristics.


Single-cell transcriptome analysis reveals T population heterogeneity and functions in tumor microenvironment of colorectal cancer metastases.
Cell mediated immune escape, a microenvironment factor, induces tumorigenesis and metastasis. The purpose of this study was to display the characteristics of T cell populations in immune microenvironments for colorectal cancer (CRC) metastasis. Unsupervised cluster analysis was conducted to identify functionally distinct T cell clusters from 3,003 cells in peripheral blood and 4,656 cells in tissues. Subsequently, a total of 8 and 4 distinct T cell population clusters were identified from tumor tissue and peripheral blood, respectively. High levels of CD8+TEX, CD4+TRM, TH1-like T cells, CD8+TEM, tumor-Treg from tissues, and CD4+TN from peripheral blood are essential components of immune microenvironment for the prediction of CRC metastasis. Moreover, exhausted T cells are characterized by higher expression of multiple inhibitory receptors, including PDCD1 and LAG3. Some genes such as PFKFB3, GNLY, circDCUN1D4, TXNIP and NR4A2 in T cells of cluster were statistically different between CRC metastasis and non-metastasis. The ligand-receptor interactions identified between different cluster cells and metastases-related DEGs identified from each cluster revealed that the communications of cells, alterations of functions, and numbers of T subsets may contribute to the metastasis of CRC. The mutation frequency of KiAA1551, ATP8B4 and LNPEP in T cells from tissues and SOR1 from peripheral blood were higher in metastatic CRC than that in non-metastatic CRC. In conclusion, the discovery of differential genes in T cells may provide potential targets for immunotherapy of CRC metastasis and relevant insights into the clinical prediction and prognosis of CRC metastasis.


Distribution of leucocyte subsets in bronchial mucosa from dogs with eosinophilic bronchopneumopathy.
Immunohistochemistry was used to characterize the distribution of leucocyte subsets in the bronchial mucosa of 11 dogs with idiopathic eosinophilic bronchopneumopathy (EBP). Formalin-fixed tissues from all dogs were included in the study, but frozen tissue from only one dog was available. MHC class II(+) cells were found in moderate numbers in the lamina propria (LP). These cells were morphologically either dendritic-like cells or macrophages, but many macrophages did not express MHC class II. Such molecules were expressed by occasional fibroblasts. L1(+) cells, which formed a relatively small component of the LP inflammatory infiltrate, were morphologically either macrophages or polymorphonuclear cells (probably eosinophils). IgA(+) plasma cells were found in varying numbers in the LP, mostly in association with glandular tissue. IgG(+) plasma cells were less common, and IgM(+) plasma cells were present in low numbers. Many CD3(+) cells were present in the LP. In the single case from which frozen tissue was available, most of the lymphocytes were labelled with CD4 marker, while smaller numbers were CD8(+) T cells. Most of the lymphocytes in this case were positively labelled with T-cell receptor (TCR)-alphabeta marker. TCR-gammadelta(+) cells, although less common, were present in significant numbers throughout the LP. CDlc(+) dendritic cells were numerous in the epithelium and in the LP, immediately beneath the basement membrane. These findings, which were similar to those described in human asthma, are suggestive of a Th2 dominant immune response in canine EBP. As in human asthma, this provides a possible basis for new forms of treatment in canine EBP.


Simultaneous determination and pharmacokinetic analysis of seven alkaloids and two flavonoids from rat plasma by HPLC-DAD after oral administration of Wuzhuyu decoction.
A simple and sensitive high-performance liquid chromatographic method was developed for the simultaneous determination and pharmacokinetic analysis of seven alkaloids dehydroevodiamine (DHED), 10-hydroxyrutaecarpine (HDR), evodiamine (EDM), rutaecarpine (RCP), 1-methyl-2-n-nonyl-4(1H)quinolone (MNQ), evocarpine (ECP), and dihydroevocarpine (DHE), and two flavonoids isorhamnetin-7-O-rutinoside (RIM) and diosmetin-7-O-β-d-glucopyranoside (GRD) in rat plasma after oral administration of Wuzhuyu decoction. The flow rate was kept at 1.0 ml/min and the detection wavelength was set at 300 nm. The calibration curves were linear in the range of 0.5013-30.076 μg/ml for DHED, 0.2161-21.608 μg/ml for RIM, 0.161-12.876 μg/ml for HDR, 0.2146-21.457 μg/ml for GRD, 2.0464-40.928 μg/ml for EDM, 1.0398-31.194 μg/ml for RCP, 0.5970-35.818 μg/ml for MNQ, 0.8371-20.928 μg/ml for ECP, and 0.5167-31.003 μg/ml for DHE. The precision (relative standard deviation (RSD), %) for all was less than 10% and the accuracy (relative error (RE), %) was within ± 10%. The results demonstrated that the assay had remarkable reproducibility with acceptable accuracy and precision. The lower limit of quantifications for the compounds in plasma ranged from 0.12 to 0.23 μg/ml and the lower limit of detections ranged from 0.024 to 0.076 μg/ml. This validated method has been successfully applied in the pharmacokinetics study of seven alkaloids and two flavonoids after orally administrating the Wuzhuyu decoction to rats.