Identification and characterisation of adducts between serum albumin and 4,4'-methylenediphenyl diisocyanate (MDI) in human plasma.
Diisocyanates are potent inducers of airways disease. Methylenediphenyl diisocyanate (MDI) is a widely used diisocyanate in the chemical industry. The aim of this study was to identify major and also immunologically relevant protein conjugates of MDI in plasma. Plasma was obtained from an MDI-exposed worker. The plasma was dialysed and then fractionated using ion exchange chromatography (IEC) and gel filtration. These fractions and also aliquots of unfractioned plasma were hydrolysed, derivatised and analysed for isocyanate adduct content using gas chromatography-mass spectrometry. In addition, immunologically relevant proteins were identified through specific IgG immunoblotting using pooled sera from two exposed workers. It was shown by dialysis that 96% of the hydrolysed MDI derivatives were protein bound and that 95% of the MDI adducts co-eluted with serum albumin in plasma using IEC. All MDI-protein adducts co-eluted with serum albumin using gel filtration. IgG immunoblotting showed a major 66 kDa protein and also some intermolecular reactions in serum albumin. This study shows serum albumin to be the major protein in plasma that forms adducts in vivo with MDI. Thus, a quick and simple quantitative method for biological monitoring may be developed for MDI exposure. The results also showed that MDI-specific IgG antibodies preferentially bind to the serum albumin in in-vitro-synthesised MDI-plasma protein conjugates.


Screening program for retinopathy of prematurity in Spain.
To prepare a retinopathy of prematurity (ROP) screening program as agreed by most of Spanish ophthalmologists dedicated to this topic. A draft of the protocol was produced taking into account the experience of the participants and current publications. This draft was corrected by all the ophthalmologists participating in the project and the final document produced was agreed by all of them. We present general guidelines to help in the screening of ROP, including treatment criteria, treatment methods, and a calendar of action. It is important to have a common working protocol in the screening of ROP to improve the action and to avoid mistakes. Although individual Hospitals may adapt the protocol to their daily activity, it is recommended that there is a minimal working protocol agreed by most of professionals dedicated to pediatric ophthalmology in Spain.


Quantifying thermal cues that initiate mass emigrations in juvenile white sharks.
While the function of migration varies among species, environmental temperature is known to be one of the most important abiotic variables that drive animal migration; however, quantifying the thresholds and timing of the cues that influence a mass emigration is difficult, often due to lack of monitoring resolution, particularly for large, highly mobile species. We used acoustic telemetry tracking and high-resolution water temperature data over a relatively large spatial scale (5.5 km2) to identify and quantify a thermal threshold for mass emigration of juvenile white sharks. Sixteen tagged sharks were observed to initiate a search for warmer water within 10-12 hours of an upwelling event where water temperatures dropped below 14 °C. Eleven sharks traveled ~ 35 km away where they experienced similar cold temperatures before returning to the aggregation site within 24 hours. Five days following the upwelling event, most sharks emigrated from the site for the season. Quantifying movement patterns across different spatial and temporal scales is necessary to understand cues and thresholds influencing animal migration, which may be greatly affected by climate anomalies and climate change, resulting in potential impacts on the dynamics of local prey species, management, and conservation policy and practice.


Comparison of surgical Limberg flap technique and crystallized phenol application in the treatment of pilonidal sinus disease: a retrospective study.
This study was designed to compare the efficacy of crystallized phenol method with Limberg flap in pilonidal sinus treatment. Patients with a diagnosis of pilonidal sinus disease treated with surgical excision + Limberg rhomboid flap technique and crystallized phenol method between 2010-2011 in the Şevket Yılmaz Training and Research Hospital, Department of General Surgery were evaluated retrospectively. Patients' age, sex, length of hospital stay, complications and recurrence rates were evaluated. Eighty eight percent of patients were male and mean age was 26.84±6.41 in the Limberg group, and 24.72±5.00 in the crystallized phenol group. Sinus orifice locations and nature, and duration of symptoms before surgery were similar in the two groups. Length of hospital stay in the Limberg group was 1.46±0.61 days; whereas all patients in the crystallized phenol group were discharged on the same day. Infection, hematoma, wound dehiscence, and cosmetic problems were significantly higher in the Limberg group. There was no difference between the two groups in terms of recurrence and seroma formation. The less invasive method of crystallized phenol application may be an alternative approach to rhomboid excision and Limberg flap in patients with non-complicated pilonidal sinus disease, yielding acceptable recurrence rates.


Intestinal barrier function in neonatal foals: options for improvement.
Gastrointestinal defence in the new-born is limited in comparison to adults, due to an immature epithelial barrier function and deficits in both innate and adaptive immune responses. Consequently, neonates (including foals) are at increased risk of disturbance to mucosal homeostasis during initial intestinal colonisation that may lead to excessive inflammation and bacterial translocation into the bloodstream, resulting in septicaemia. Bacterial recognition by Pattern Recognition Receptors (PRRs) and their downstream regulation of cytokine release have been shown to be pivotal for gastrointestinal mucosal homeostasis and the development of a functional intestinal barrier. Evidence suggests that selective PRR agonists limit the inflammatory responses and improve epithelial barrier function. Milk, and in particular colostrum, contain a broad array of oligosaccharides which seem to act as PRR agonists. This class of compounds forms a source for new dietary formulas that may orchestrate gut colonisation by the commensal flora in the early phase of life and so reduce the risks of inflammation and pathogen invasion.


The in vitro efficacy of deltamethrin and alpha-cypermethrin against engorged female Haemaphysalis qinghaiensis ticks (Acari: Ixodidae).
Currently, the most efficient and widely used method for tick control is the application of acaricides, especially deltamethrin and alpha-cypermethrin, two pyrethroids with neurotoxic action. In this study, the in vitro efficacy of deltamethrin and alpha-cypermethrin was assessed on engorged female Haemaphysalis qinghaiensis ticks. An in vitro bioassay (adult immersion test) was carried out to determine the LC (lethal concentration) 50 and LC90 of both compounds, calculated by probit analysis. The LC50 and LC90 values of deltamethrin and alpha-cypermethrin were 5.67 (LC50) and 51.72ppm (LC90), and 166.56 (LC50) and 1366.69ppm (LC90), respectively. This study provides important information on the efficacy of deltamethrin and alpha-cypermethrin for the control of H. qinghaiensis.


Leucocytosis as a marker of organ damage induced by chronic strenuous physical exercise.
The effects of strenuous physical exercise on the serial changes in the haematological, biochemical and hormonal markers were investigated. A group of 14 soldiers, aged 24-36 years, took part in a military training course for about 13 weeks. After severe exercise stress, an increase (90%) in the number of peripheral blood leucocytes was observed. The degree of leucocytosis showed a close correlation with the values of some serum parameters, such as concentrations of aspartate aminotransferase (AST; r = 0.747), lactate dehydrogenase (LD; r = 0.748), blood urea nitrogen (r = 0.756), creatine kinase (CK; r = 0.637), manganese-superoxide dismutase (Mn-SOD; r = 0.508), alanine aminotransferase (ALT; r = 0.542) and uric acid (r = 0.538), and concentrations of urinary parameters, such as vanilmandelic acid (r = 0.429) and free cortisol (r = 0.437). The subjects showing prominent leucocytosis over 9500 cells.microliters-1 exhibited a lower concentration of serum cholinesterase than those who showed milder leucocytosis. The serum Mn-SOD concentration was closely correlated with the serial changes in serum concentrations of AST, ALT, LD and CK, indicating exercise-induced muscle and liver damage. The change in peripheral leucocyte number was assumed to be diagnostically informative and may be a prognostic marker, reflecting organ damage and restoration after strenuous physical exercise.


Single-session intense pulsed light combined with stable fixed-dose triple combination topical therapy for the treatment of refractory melasma.
The effectiveness of intense pulsed light (IPL) has been reported in adults with melasma, but there is little information about IPL with triple combination topical therapy (TC) and refractory melasma. Sixty-two patients with totally or partially refractory melasma were enrolled in this randomized open-label study. Thirty-one patients were treated with IPL in a single session, bleaching agents and broad-spectrum sunscreens. Thirty-one patients were in the control group, receiving only bleaching agents and broad-spectrum sunscreens. The Melasma Area and Severity Index (MASI) and the investigator's global assessment using a seven-point scale were used to determine the impact and effectiveness of the treatment. The IPL group results based on MASI showed a 49.4% reduction (from 17.6 to 8.9; p < 0.001) after six months and a 44.9% reduction after 12 months (from 17.6 to 9.7; p < 0.001). The investigator's global assessment showed that the difference in the improvement rate between the IPL group and control group was significant (p = 0.002), with a better response in the IPL group. Single session IPL combined with stable fixed-dose triple combination treatment is a safe and effective treatment for refractory mixed and dermal melasma.


Interventions to Improve the Quality in the Organ and Tissue Donation Process.
Map Interventions is capable of supporting the multidisciplinary team that works in organ and tissue donation to disseminate quality in this process. A scoping review study that was conducted through the steps proposed by the Joanna Briggs Institute. Fifty-six studies made up the sample. 2018 (no. 07, 12.5%) had the highest number of publications. The country that published the most was the United States (no. 16, 28.56%). The database with the most publications was the Cumulative Index to Nursing and Allied Health Literature - CINAHL (no. 15, 26.78%). The most used interventions, which had the most significant impact on the improvement of results and quality, were the use of indicators in all stages of the organ and tissue donation process; the use of real goals that can be achieved; frequent audits, validation of instruments to track opportunities for improvement; as well as methodologies to implement quality and education among professionals who work in this process. Such interventions reveal important changes in the organ donation process, especially in the notification of potential and effective donors, as well as providing an opportunity for safety in the stages of the organ and tissue donation process. The interventions tracked suggest the implementation of a set of actions formed by the continuous use of auditing, indicators, continuing education with the team that works in the process of organ and tissue donation, combined with the management of the results obtained through the indicators, where it is generated from these data, actions that have a direct impact on the weaknesses identified.


The rheumatoid heel: its relationship to other disorders in the rheumatoid foot.
Four-hundred and eight rheumatoid feet are studied. The percentage of talalgia is 3.7%; for inferior exostosis it is 29.6%, and 30.8% for posterior exostosis. Posterior demineralisation is present in 12%, whereas for bony erosion it is 8.1%. Plantar spurs are very closely associated to flattened feet (p less than 0.0001). Likewise a very noticeable statistical association is noted between postero-superior calcaneitis and tarsal arthritis (p less than 0.0001), and calcaneitis was more frequent among marked valgus (p less than 0.001). These results are compared with findings of other works. Therapeutic consequences are evoked.


MRI diagnosis of Takayasu arteritis in a young woman.
Takayasu arteritis is a rare type of chronic, granulomatous vasculitis, characterized by inflammation of blood vessels of large caliber, such as the aorta, and its branches. Clinical presentation varies, depending on the severity of symptoms. Onset may be gradual, however at times, presentation may be acute, and life threatening. Herein, we present the case of a 29-year-old female, 3 months post-op, following a right carotid artery stenting procedure. The patient presented with nonspecific symptoms of malaise, arthralgia, and blurry vision. Clinical presentation and imaging findings were consistent with Takayasu's Arteritis.


Moxifloxacin (BAY12-8039), a new 8-methoxyquinolone, is active in a mouse model of tuberculosis.
Moxifloxacin (BAY12-8039) is a new 8-methoxyquinolone shown to be active against Mycobacterium tuberculosis in vitro. We tested moxifloxacin for activity in mice against M. tuberculosis CSU93, a highly virulent, recently isolated clinical strain. The MIC of moxifloxacin for the CSU93 strain was 0.25 microg/ml. The serum moxifloxacin concentration after oral administration in mice peaked within 0.25 h, reaching 7.8 microg/ml with doses of 100 mg/kg of body weight; the maximum concentration and the analysis of the area under the concentration-time curve revealed dose dependency. When mice were infected with a sublethal inoculum of mycobacteria and then treated with moxifloxacin at 100 mg/kg per day for 8 weeks, the log10 CFU counts in the organs of treated mice were significantly lower than those for the control group (0.6 +/- 0.2 versus 5.6 +/- 0. 3 in the lungs and 1.5 +/- 0.7 versus 4.9 +/- 0.5 in the spleens, respectively; P < 0.001 in both organs). The effectiveness of moxifloxacin monotherapy was comparable to that seen in mice receiving isoniazid alone. Combination therapy with moxifloxacin plus isoniazid was superior to that with moxifloxacin or with isoniazid alone in reducing bacillary counts in the organs studied. Using a sensitive broth-passage subculture method, we demonstrated that 8 weeks of treatment with moxifloxacin (100 mg/kg per day) or with moxifloxacin plus isoniazid (100 mg/kg and 25 mg/kg, respectively, per day) sterilized the lungs in seven of eight and in eight of eight mice, respectively. Among surviving bacilli isolated from animals infected with a high-titer inoculum and treated for 7 weeks with low-dose moxifloxacin (20 mg/kg per day), breakthrough resistance to moxifloxacin was not observed. These results indicate that moxifloxacin is highly effective in reducing M. tuberculosis infection in mice and has activity comparable to that of isoniazid. Combination therapy with moxifloxacin and isoniazid was highly effective, suggesting that moxifloxacin may be useful in multiple-drug regimens for human tuberculosis.


Slice-based and time-specific hemodynamic measurements discriminate carotid artery vulnerable atherosclerotic plaques.
Hemodynamic patterns play key roles in progression of carotid vulnerable plaques. However, most of previous studies utilized maximum or averaged value of hemodynamic measurements which is not an ideal representative of hemodynamic patterns. This study aimed to investigate the association of slice-based and time-specific hemodynamic measurements with carotid vulnerable plaque using magnetic resonance (MR) vessel wall imaging and histology. Thirty-two patients (mean age: 63.9±8.1 years; 25 males) with carotid atherosclerotic stenosis (≥50% stenosis) referred to carotid endarterectomy were recruited and underwent MR vessel wall imaging. Carotid plaque burden was evaluated on MR images and vulnerable plaque features including calcification, lipid-rich necrotic core, and intra-plaque hemorrhage (IPH) were identified by histology. The slice-based and time-specific hemodynamic measurements were extracted from computational fluid dynamics simulation of 3D carotid arterial model. Correlation coefficients between hemodynamic measurements and carotid plaque features were calculated and the logistic regressions with generalized estimating equation (GEE) were conducted. The value in discriminating carotid vulnerable plaque features was determined by receiver-operating-characteristic analysis. Of 102 MR-histology matched slices from 32 patients, time-averaged wall shear stress (TAWSS) (r=0.263, p=0.008), oscillatory shear index (OSI) (r=-0.374, p<0.001), and peakWSS (r=0.232, p=0.019) were significantly associated with carotid IPH. The logistic regression with GEE revealed that peakWSS (OR, 1.206; 95% CI, 1.026-1.418; p, 0.023) and TAWSS (OR, 0.364, 95% CI, 0.138-0.959; p, 0.041) were significantly associated with presence of IPH after adjusting for age and BMI. In discriminating carotid IPH, the AUC of TAWSS, OSI, combined TAWSS with maximum wall thickness (MWT) and combined OSI with MWT was 0.656, 0.722, 0.761, and 0.764, respectively. Slice-based and time-specific hemodynamic characteristics could effectively discriminate carotid IPH. Combination of hemodynamic measurements with carotid plaque burden might be a stronger indicator for carotid vulnerable plaque features than each measurement alone.


Tissue engineered skin substitutes: A comprehensive review of basic design, fabrication using 3D printing, recent advances and challenges.
The multi-layered skin structure includes the epidermis, dermis and hypodermis, which forms a sophisticated tissue composed of extracellular matrix (ECM). The wound repair is a well-orchestrated process when the skin is injured. However, this natural wound repair will be ineffective for large surface area wounds. Autografts-based treatment is efficient but, additional pain and secondary healing of the patient limits its successful application. Therefore, there is a substantial need for fabricating tissue-engineered skin constructs. The development of a successful skin graft requires a fundamental understanding of the natural skin and its healing process, as well as design criteria for selecting a biopolymer and an appropriate fabrication technique. Further, the fabrication of an appropriate skin graft needs to meet physicochemical, mechanical, and biological properties equivalent to the natural skin. Advanced 3D bioprinting provides spatial control of the placement of functional components, such as biopolymers with living cells, which can satisfy the prerequisites for the preparation of an ideal skin graft. In this view, here we elaborate on the basic design requirements, constraints involved in the fabrication of skin graft and choice of ink, the probable solution by 3D bioprinting technique, as well as their latest advancements, challenges, and prospects.


Developing skills learning in obstetric nursing: approaches between theory and practice.
To analyze the development of professional skills in an obstetric nursing graduate course. Qualitative research, applying semi-structured interviews with 11 students in the obstetric nursing specialization at the State University of Ceará. Data was submitted to thematic review. According to the subjects, the course offers the development of skills to strengthen and expand the range of activities in obstetric nursing. Despite relying on previous knowledge and experience acquired by the students, there is a gap between the content taught and internship practice, presented as challenges and difficulties faced by the students. The findings suggest a need for curricular revision, incorporating active teaching-learning methodologies, to overcome the disjunction between theory and practice. Students are part of a corpus that is potentially implicated in the construction and transformation of thoughts and values set forth by educational and health institutions, and it is necessary to make changes in political and social organizations, with a focus on providing comprehensive and egalitarian care to the population. Analisar o desenvolvimento de competências profissionais em curso de pós-graduação em Enfermagem Obstétrica. Pesquisa qualitativa, utilizando entrevista semiestruturada com 11 egressos da especialização em Enfermagem Obstétrica da Universidade Estadual do Ceará. Dados submetidos à análise temática. Na ótica dos sujeitos, o curso confere o desenvolvimento de competências que fortalecem e ampliam o campo de atuação da enfermagem obstétrica. Embora resgate o conhecimento prévio dos discentes e as experiências vivenciadas, há distanciamento entre conteúdos ministrados e a prática de estágios, apresentados como desafios e dificuldades enfrentadas pelos egressos. Os achados sugerem revisão curricular, incorporando as metodologias ativas de ensino-aprendizagem, superando a fragmentação entre teoria e prática. Os egressos se constituem em um corpus potencialmente implicado na construção e transformação de pensamentos e valores das instituições de saúde e ensino, necessários às mudanças nas organizações políticas e sociais, visando atendimento integral e igualitário à população.


Efficacy of prilocaine-lidocaine cream in the treatment of premature ejaculation.
We evaluated the efficacy of a new lidocaine-prilocaine cream in preventing premature ejaculation. An open pilot, unblinded study was done using lidocaine-prilocaine cream in 11 healthy, married men with premature ejaculation without organic or erectile problems. The patients were instructed to apply 2.5 gm. of the cream 30 minutes before sexual contact and to cover the penis with a condom. Patients were asked to grade the effect of the cream on ejaculation after each application. There was a significant improvement in premature ejaculation statistically and clinically. Five patients graded the result as excellent compared to baseline, 4 graded it as better and 2 claimed to have no change compared to ejaculation before use of the cream. No adverse effects were noted. These promising results should prompt a large double-blind placebo-controlled trial. If confirmed, this therapy may be a breakthrough in the treatment of the most common form of male sexual dysfunction.


Independent effects of amyloid and vascular markers on long-term functional outcomes: An 8-year longitudinal study of subcortical vascular cognitive impairment.
Subcortical vascular cognitive impairment (SVCI) is characterized by the presence of cerebral small vessel disease (CSVD) markers. Some SVCI patients also show Alzheimer's disease and cerebral amyloid angiopathy markers. However, the effects of these imaging markers on long-term clinical outcomes have not yet been established. The present study, therefore, aimed to determine how these imaging markers influence functional disability and/or mortality. We recruited 194 participants with SVCI from the memory clinic and followed them up. All participants underwent brain magnetic resonance imaging at baseline, and 177 (91.2%) participants underwent beta-amyloid (Aβ) positron emission tomography. We examined the occurrence of ischemic or hemorrhagic strokes. We also evaluated functional disability and mortality using the modified Rankin scale. To determine the effects of imaging markers on functional disability or mortality, we used Fine and Gray competing regression or Cox regression analysis. During a 8.6-year follow-up period, 46 of 194 patients (23.7%) experienced a stroke, 110 patients (56.7%) developed functional disabilities and 75 (38.6%) died. Aβ positivity (subdistribution hazard ratio [SHR] = 2.73), greater white matter hyperintensity (WMH) volume (SHR = 3.11) and ≥3 microbleeds (SHR = 2.29) at baseline were independent predictors of functional disability regardless of the occurrence of stroke. Greater WMH volume (hazard ratio = 2.07) was an independent predictor of mortality. Our findings suggest that diverse imaging markers may predict long-term functional disability and mortality in patients with SVCI, which in turn may provide clinicians with a more insightful understanding of the long-term outcomes of SVCI.


Severe congenital neutropenia with neurological impairment due to a homozygous VPS45 p.E238K mutation: A case report suggesting a genotype-phenotype correlation.
VPS45 mutations cause severe congenital neutropenia (SCN). We report on a girl with SCN and neurological impairment harboring a homozygous p.E238K mutation in VPS45 (vacuolar sorting protein 45). She successfully underwent hematopoietic stem cell transplantation. Our findings delineate the phenotype and indicate a possible genotype-phenotype correlation for neurological involvement.


Pyloro-duodenal hernia with formation of enterocutaneous fistula in a buffalo calf following a dog attack.
A body wall hernia entrapping abomasum and concurrent duodenal fistula in a buffalo calf aged about 8 months, secondary to a dog bite was successfully treated by closure of fistulous orifice and ventro lateral herniorrhaphy.


Antidepressant-like effects of the vasopressin V1b receptor antagonist SSR149415 in the Flinders Sensitive Line rat.
There is an increased interest in the potential of vasopressin receptor antagonists as antidepressants because of the involvement of vasopressin in stress-related behavioral changes. The present study sought to provide confirmatory evidence for the antidepressant-like effects of the selective vasopressin V1b receptor antagonist SSR149415, which had been previously demonstrated in a variety of animal models. The Flinders Sensitive Line (FSL) rat, a selectively bred animal model of depression, was chronically treated for 14 days with SSR149415 (1, 10, and 30 mg/kg), vehicle, or desipramine (5 mg/kg) as a positive control. Approximately 22-24 h after the last treatment, the rats were exposed to a single 5-min session in a cylinder containing 25 degrees C water and immobility was recorded. A control group of Flinders Resistant Line (FRL) rats was included as a reference group as well as one treated with 10 mg/kg SSR149415. Vehicle-treated FSL rats exhibited much more immobility than the FRL rats, and desipramine-treated FSL rats had much lower scores, as expected. Treatment with SSR149415 reduced immobility in the FSL rats at all doses, but only the higher doses reduced it such that they were no longer different from the FRL rats. In contrast, SSR149415 did not alter the lower immobility of the FRL rats. The social interaction test of anxiety was also examined in the FSL rats, at 20-22 h after the last of the 14 injections. Results showed that the 10 and 30 mg/kg doses of SSR149415 increased the time spent in social interaction in the FSL rats, suggesting anxiolytic effects. These findings confirm the antidepressant-like potential of SSR149415 and suggest that it may also have anxiolytic effects. It is likely that the strategy of testing selective vasopressin V1b receptor antagonists will be fruitful.


Characterization by high performance liquid chromatography of nuclear metabolites of testosterone in the brains of male rhesus monkeys.
Testosterone (T) restores the potency of castrated male rhesus monkeys, and our autoradiographic data have demonstrated that 3H-T or its metabolites concentrate in cell nuclei in the corticomedial amygdala, bed nucleus of stria terminalis, preoptic area, and hypothalamus. In rat, 3H-estradiol (3H-E2) is a major nuclear metabolite of 3H-T in areas of the limbic system, but comparable data are lacking for the primate. We have therefore developed an improved technique using high performance liquid chromatography for investigating metabolites of 3H-T that accumulate in cell nuclei in small amounts of tissue obtained from the brain of the rhesus monkey. Two castrated male rhesus monkeys were injected with 5 mCi of 3H-T and were killed 30 min later. In amygdala, preoptic area-bed nucleus of stria terminalis, and hypothalamus, 48-70% of the nuclear radioactivity was in the form of 3H-E2 (Type I tissues). In six other brain areas and in pituitary, 35-85% of the nuclear radioactivity was in the form of 3H-T (Type II tissues), whereas in genital tract tissues, 86-99% of the nuclear radioactivity was in the form of 3'-dihydrotestosterone (3H-DHT) (Type III tissues). In plasma and in supernatants from both Type I and Type II tissues, the proportions of 3H-T were high, and 3H-E2 did not exceed 10% of the total extractable radioactivity. These data suggest that, as in rodents, some of the central actions of T in primates may be mediated by estrogen target neurons.


Risk Factors for Palbociclib-Induced Early Developing Neutropenia in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.
This study aimed to determine the risk factors for palbociclib-induced grade 4 or grade 3 neutropenia (NP) requiring dose reduction or delayed treatment in patients with HR+/HER2-metastatic breast cancer in the first 3 cycles (early grade 3/4 NP) and whether the early developing grade 3/4 NP affects progression-free survival. A retrospective study using electronic medical records was conducted on patients who received palbociclib for metastatic breast cancer between January 2018 and August 2022. The early grade 3/4 NP risk factors were evaluated with univariate and multivariable logistic regression analyses. In addition, the Kaplan-Meier method was used to estimate the median progression-free survival (PFS) to analyze the effect of early grade 3/4 NP on treatment. Out of the 264 patients included in this study, 173 (65.6%) experienced early grade 3/4 NP. A total of four models were applied for multivariable analysis to identify early grade 3/4 NP-developing factors. Low baseline ANC, WBC, PLT, and BSA were significant risk factors for early grade 3/4 NP; baseline ANC < 3700/mm3, WBC < 6.30 × 109/mm3, PLT < 230 × 109/mm3, and BSA < 1.58 m2 increased the risk by approximately 4.0-fold, 3.7-4.0-fold, 2.1-fold, and 2.0-fold, respectively. Early grade 3/4 NP did not affect PFS (p = 0.710), although patients with early grade 3/4 NP had more frequent dose reductions or treatment delays. Based on the results, low baseline ANC, WBC, PLT, and BSA were associated with early grade 3/4 NP. Patients with risk factors require careful monitoring, and this study is expected to help predict NP, which may appear in early treatment.


Blood distribution of tenoxicam in humans: a particular HSA drug interaction.
Blood binding of tenoxicam was studied in vitro by equilibrium dialysis. Isolated human plasma proteins and blood cells were checked, and the distribution of the bound form was then calculated. The results showed that tenoxicam is mainly bound to HSA and that binding percentages are not different when measured in plasma (98.4%) and in an HSA solution at physiological concentration (704 microM, 98.15%). In these conditions, within the range of 1-150 microM, the tenoxicam binding percentage remained constant, evidence of a nonsaturable process. When a lower HSA concentration (10 microM) was used, the binding parameters of the tenoxicam interaction were calculated by using the same equilibrium dialysis data, by 3 methods of analysis- a stoichiometric method and site-oriented methods, fixing or not the number of HSA binding sites (n) as integer values. The best fit was observed with the first method, suggesting that two main interactions occurred. The site-oriented method gave lesser fits, the better being observed when n was not fixed. Its value, 1.77, suggest the possibility of two binding sites, one of them not preformed. The effects of known markers of site I, warfarin and apazone, of site II, diazepam and ibuprofen and of palmitic acid showed that tenoxicam is bound simultaneously to both sites I and II. The binding capacity of site I for tenoxicam is enhanced by diazepam: as this compound alone is bound to site II, this result suggests that the two HSA binding sites are not independent.


Production of (-)-mitorubrinic acid byPenicillium vermiculatum.
Biosynthesis of (-)-mitorubrinic acid and (-)-vermistatin byPenicillium vermiculatum strain IV/5 was stimulated by high concentration of glucose and urea as a C and N source, respectively. Effect of phosphate, trace elements and organic acids was also studied.


Results of two consecutive treatment protocols in Polish children with acute lymphoblastic leukemia.
The aim of the study was to retrospectively compare the effectiveness of the ALL IC-BFM 2002 and ALL IC-BFM 2009 protocols and the distribution of risk groups by the two protocols after minimal residual disease (MRD) measurement as well as its impact on survival. We reviewed the medical records of 3248 patients aged 1-18 years with newly diagnosed ALL who were treated in 14 hemato-oncological centers between 2002 and 2018 in Poland. The overall survival (OS) of 1872 children with ALL treated with the ALL IC 2002 protocol was 84% after 3 years, whereas the OS of 1376 children with ALL treated with the ALL IC 2009 protocol was 87% (P < 0.001). The corresponding event-free survival rates were 82% and 84% (P = 0.006). Our study shows that the ALL IC-BFM 2009 protocol improved the results of children with ALL compared to the ALL IC-BFM 2002 protocol in Poland. This analysis confirms that MRD marrow assessment on day 15 of treatment by FCM-MRD is an important predictive factor.


The treatment of acute lymphoblastic leukemia in Jehovah's Witnesses and patients who cannot accept blood products.
Jehovah's Witnesses cannot accept blood products based upon religious beliefs, and when they present with acute leukemia, the ideal treatment strategy can be controversial. We present six cases of Jehovah's Witnesses with acute lymphoblastic leukemia and show that complete remission can be achieved without using anthracycline in 83% (5/6) of patients. We also report, for the first time in this population, that the use of agents with novel mechanisms of action, such as blinatumomab and nelarabine, is associated with minimal myelosuppression and can produce durable responses, with 2 of 6 patients still alive in CR3 at 4.9 and 6.6 years.


Psychological effects of a short behavior modification program in patients with acute myocardial infarction or coronary artery bypass grafting. A randomized controlled trial.
The effects of a short intervention on behavioral risk factor modification in patients with coronary artery disease (CAD) on Type A behavior, vital exhaustion, and depression were studied in a randomized controlled trial. Acute myocardial infarction patients or patients who underwent coronary artery bypass grafting (CABG) were randomly assigned to an 8-week multiple risk modification group program (n = 94) or to a control group (n = 90) that received usual care with standard physical exercise training. Patients were assessed before intervention, directly after intervention, and at 9-month follow-up. The intervention was effective in reducing hostility and total Type A behavior at postintervention (P = .01) and at 9-month follow-up (P = .03). The intervention had no overall impact on vital exhaustion and depression, measured by the Beck Depression Inventory (BDI), whereas we unexpectedly found that the percentage of patients with major depression was reduced in the control group but not in the intervention group. The results indicate that a short behavioral intervention for coronary patients can result in relatively large and persistent reductions in cognitive aspects of Type A behavior and hostility, in particular. In view of the unwanted findings on the diagnosis of depression, however, we do not unequivocally advise the intervention to the general population of AMI and CABG patients.


Spectral expansion and antenna reduction can enhance photosynthesis for energy production.
We consider two approaches for improving the efficiency of photosynthesis: the expansion of the solar spectrum that drives oxygenic photosynthesis and the reduction of antenna systems that couple to the photochemical reaction center. The first approach can possibly result in an increase of 19% in the number of photons available per unit area if the photosynthetically active radiation spectrum is expanded to 750 nm. The second approach can in principle shift the photosynthesis light response curve to significantly higher intensities, thereby reducing the amount of excess light, which is absorbed photons in excess of the number that can be utilized. The implementation of these approaches may lead to apparent improvement in photosynthetic efficiency in many but not all the cases.


Effect of Sodium-Glucose Co-transporter-2 Inhibitors on Ventricular Repolarization Markers in Heart Failure with Reduced Ejection Fraction.
Sodium-glucose co-transporter-2 (SGLT2) inhibitors added to optimal medical therapy have been shown to reduce the risk of cardiovascular death and recurrent heart failure (HF) hospitalization in HF patients. We aimed to evaluate the effect of SGLT2 inhibitors on the ventricular repolarization markers (VRM) in patients with HF with reduced ejection fraction (HFrEF). 51 patients with HFrEF who had symptoms New York Heart Association (NYHA) class II-IV despite optimal medical treatment and were added SGLT2 inhibitors to their treatment were included in the study. Electrocardiography (ECG) and laboratory results obtained before the treatment and at the first-month follow-up visit were compared. QT, QTc (corrected by Bazett formula), QT dispersion (QTd), QTc dispersion (QTc-d), Tpeak to Tend (Tp-e) interval, Tp-e/QT, and Tp-e/QTc ratios were measured and defined as VRM. A significant decrease was observed in HR, QT, QTc intervals, and QTd compared to pre-treatment. While the mean Tp-e interval was 101.5 ± 11.7 ms before treatment, it decreased to 93.1 ± 12.7 ms after treatment (p < 0.001). There was a significant decrease in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels after treatment [2859 ± 681vs.1266 ± 763, respectively (p < 0.001)] and QTd, Tp-e interval, and Tp-e/QTc ratio was positively correlated with the change in NT-proBNP level. The addition of SGLT2 inhibitors to optimal medical therapy in HFrEF patients positively changes VRM (QT, QTc, QTd, Tp-e, and Tp-e/QTc).


[Study under scanning electron microscopy of scales of PUVA treated psoriasis (authors's transl)].
The authors recall an particular aspect of microvilli at the surface of horney cells in psoriasic disease. These microvilli are rounded, irregular size and spaced. The photochemotherapy involves parallely the disappearance of these microvilli and the recovery of the cutaneous lesions. The authors describe a "crumpled" aspect of the microvilli, appearing during the evolution towards the recovery.


Pediatric Odontogenic Cysts of the Jaws.
Odontogenic cysts represent a common form of pathology of the jaws, and the natural history, clinicopathologic findings, and appropriate management strategies are important to the oral and maxillofacial surgeon. Odontogenic cysts in the pediatric populations are important pathologic entities given their potential impact on the growth and development of the maxillofacial complex. Inappropriate management strategies can severely affect the form and function of the growing child. Categorizing pediatric odontogenic cysts into inflammatory or developmental causes provides a convenient way of conceptualizing these various entities and helps facilitate the appropriate diagnosis and the subsequent management.


Anomalous origins of the right vertebral, subclavian, and common carotid arteries in a patient with a four-vessel aortic arch.
Many anomalies of the aortic arch and great vessels are uncovered as serendipitous findings on imaging studies, in the anatomy laboratory, or at surgery. A 56-year-old man had an arch angiogram as part of an evaluation for cerebrovascular disease. A four-vessel left aortic arch was identified consisting of the right carotid, left carotid, right subclavian, and left subclavian arteries. The right common carotid gave rise to the right vertebral artery in the chest while the normally located left vertebral arose from the left subclavian artery. No aneurysm or aortic diverticulum was identified.


Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature.
Metolazone is a potent thiazide-like diuretic. It is recommended in severe congestive heart failure (HF). We conducted a review of the existing literature and found that the available information on the use of metolazone in HF is based on studies containing less than 250 patients in total. Nevertheless, metolazone is widely used, often in combination with a loop diuretic. Absorption of metolazone seems to be reduced in HF. Metolazone produces a diuretic response despite a low glomerular filtration rate. A wide dose range of metolazone has been investigated (< or =2.5 to 200 mg), leaving no clear dosing recommendation. However, in most studies a low starting dose (< or =5 mg) was used. We further report an observational study on 21 patients with refractory systolic HF from our specialized outpatient HF clinic. The aim was to evaluate the effects of metolazone in combination with a loop diuretic in contemporary HF patients. We registered 42 episodes of treatment with metolazone. The maximal dose of metolazone was 5 mg. NYHA functional class improved. A significant reduction during treatment in weight, blood pressure, plasma-sodium and -potassium was seen whereas plasma-BUN and -creatinine increased significantly. Clinically important hypokalemia (<2.5 mM) or hyponatremia (<125 mM) were observed during 10% of the treatment episodes. The literature review and the observational study support the use of low-dose metolazone (< or =5 mg) on top of oral loop diuretics, as an effective and relatively safe treatment in contemporary outpatients with refractory HF.


A case-control pilot study of low-intensity IVF in good-prognosis patients.
Low-intensity IVF (LI-IVF) is rapidly gaining in popularity. Yet studies comparing LI-IVF to standard IVF are lacking. This is a case-control pilot study, reporting on 14 first LI-IVF and 14 standard IVF cycles in women with normal age-specific ovarian reserve under age 38, matched for age, laboratory environment, staff and time of cycle. LI-IVF cycles underwent mild ovarian stimulation, utilizing clomiphene citrate, augmented by low-dose gonadotrophin stimulation. Control patients underwent routine ovarian stimulation. LI-IVF and regular IVF patients were similar in age, body mass index, FSH and anti-Müllerian hormone. Standard IVF utilized more gonadotrophins (P<0.001), yielded more oocytes (P<0.001) and cryopreserved more embryos (P<0.001). With similar embryo numbers transferred, after ethnicity adjustments, standard IVF demonstrated better odds for pregnancy (OR 7.07; P=0.046) and higher cumulative pregnancy rates (63.3% versus 21.4%; OR 6.6; P=0.02). Adjustments for age, ethnicity and diagnosis maintained significance but oocyte adjustment did not. Cost assessments failed to reveal differences between LI-IVF and standard IVF. In this small study, LI-IVF reduced pregnancy chances without demonstrating cost advantages, raising questions about its utility. In the absence of established clinical and/or economic foundations, LI-IVF should be considered an experimental procedure. Low-intensity IVF (LI-IVF) is increasingly propagated as an alternative to standard IVF. LI-IVF has, however, never been properly assessed in comparison to standard IVF. Such a comparison is presented in the format of a small pilot study, matching LI-IVF cycles with regular IVF cycles and comparing outcomes as well as costs. The study suggests that LI-IVF, at least in this setting, is clinically inferior and economically at best similar to standard IVF. LI-IVF should, therefore, as of this point not be offered as routine IVF treatment but only as an experimental procedure.


The impact of testosterone imbalance on depression and women's health.
Women suffer more often from depression than males, indicating that hormones might be involved in the etiology of this disease. Low as well as high testosterone (T) levels are related to depression and well-being in women, T plasma levels correlate to depression in a parabolic curve: at about 0.4-0.6 ng/ml plasma free T a minimum of depression is detected. Lower levels are related to depression, osteoporosis, declining libido, dyspareunia and an increase in total body fat mass. Androgen levels in women decrease continuously to about 50% before menopause compared to a 20-year-old women. Androgen levels even decline 70% within 24 h when women undergo surgical removal of the ovaries. Conventional oral contraception or HRT cause a decline in androgens because of higher levels of SHBG. Hyperandrogenic states exist, like hirsutism, acne and polycystic ovary syndrome. Social research suggests high androgen levels cause aggressive behavior in men and women and as a consequence may cause depression. Higher androgen values are more pronounced at young ages and before and after delivery of a baby and might be responsible for the "baby blues". It was found that depression in pubertal girls correlated best with an increase in T levels in contrast to the common belief that "environmental factors" during the time of growing up might be responsible for emotional "up and downs". T replacement therapy might be useful in perimenopausal women suffering from hip obesity, also named gynoid obesity. Abdominal obesity in men and women is linked to type 2 diabetes and coronary heart diseases. Testosterone replacement therapy in hypoandrogenic postmenopausal women might not only protect against obesity but also reduce the risk of developing these diseases. Antiandrogenic progestins might be useful for women suffering from hyperandrogenic state in peri- and postmenopause. Individual dosing schemes balancing side effects and beneficial effects are absolutely necessary. Substantial interindividual variability in T plasma values exists, making it difficult to utilize them for diagnostic purposes. Therefore a "four-level-hormone classification scheme" was developed identifying when estradiol (E) and T levels are out of balance. (1) Low E-low T levels are correlated with osteoporosis, depression, and obesity; (2) high E-low T with obesity, decreased libido; (3) high T-low E levels with aggression, depression, increased libido, and substance abuse; (4) high E-high T with type II diabetes risk, breast cancer and cardiovascular risk. Testosterone delivery systems are needed where beneficial and negative effects can be balanced. Any woman diagnosed for osteoporosis should be questioned for symptoms of depression.


[Histopathology studies on 8,673 cases of ocular adnexal hyperplastic lesions and tumors].
To study the histopathologic classification of ocular adnexal hyperplastic lesions and tumors according to the histogenesis and the anatomic sites. To analyze retrospectively the pathologic specimens of 8,673 cases of ocular adnexal hyperplastic lesions and tumors between 1961 - 1997. There were 7,265 benign cases (83.77%), and 1,408 malignant cases (16.23%). Classification by anatomic sites: eye lid 5,313 cases (61.26%), orbit 1,484 cases (17.11%) and epibulbar 1,876 cases (21.63%). Classification by histogenesis: (1) Primary tumor 6,679 cases: epitheliogenic 2,481 cases (37.15%), mesenchymal 753 cases (11.27%), lympho-hematopoietic 102 cases (1.53%), neurogenic 1,542 cases (23.09%), congenital abnormal embryogenetic 1,767 cases (26.46%), uncertain resource tumor 34 cases (0.50%). (2) Secondary tumor 13 cases; (3) Metastatic tumor 9 cases; (4) Non-tumor lesion 1,972 cases. The classification is helpful to the histopathologic diagnosis and the study about the detailed distribution of common ocular adnexal hyperplastic lesions and rare tumors, and it also increases the pathologic diagnostic data in North China.


Functional inositol 1,4,5-trisphosphate receptors assembled from concatenated homo- and heteromeric subunits.
Vertebrate genomes code for three subtypes of inositol 1,4,5-trisphosphate (IP3) receptors (IP3R1, -2, and -3). Individual IP3R monomers are assembled to form homo- and heterotetrameric channels that mediate Ca(2+) release from intracellular stores. IP3R subtypes are regulated differentially by IP3, Ca(2+), ATP, and various other cellular factors and events. IP3R subtypes are seldom expressed in isolation in individual cell types, and cells often express different complements of IP3R subtypes. When multiple subtypes of IP3R are co-expressed, the subunit composition of channels cannot be specifically defined. Thus, how the subunit composition of heterotetrameric IP3R channels contributes to shaping the spatio-temporal properties of IP3-mediated Ca(2+) signals has been difficult to evaluate. To address this question, we created concatenated IP3R linked by short flexible linkers. Dimeric constructs were expressed in DT40-3KO cells, an IP3R null cell line. The dimeric proteins were localized to membranes, ran as intact dimeric proteins on SDS-PAGE, and migrated as an ∼1100-kDa band on blue native gels exactly as wild type IP3R. Importantly, IP3R channels formed from concatenated dimers were fully functional as indicated by agonist-induced Ca(2+) release. Using single channel "on-nucleus" patch clamp, the channels assembled from homodimers were essentially indistinguishable from those formed by the wild type receptor. However, the activity of channels formed from concatenated IP3R1 and IP3R2 heterodimers was dominated by IP3R2 in terms of the characteristics of regulation by ATP. These studies provide the first insight into the regulation of heterotetrameric IP3R of defined composition. Importantly, the results indicate that the properties of these channels are not simply a blend of those of the constituent IP3R monomers.


Efficacy of mesenchymal stem cell therapy on glucose levels in type 2 diabetes mellitus: A systematic review and meta-analysis.
In recent years, mesenchymal cellular therapies have received much attention in the treatment of diabetes. In this meta-analysis, we aimed to evaluate the efficacy of mesenchymal stem cell therapy in type 2 diabetes mellitus patients. A comprehensive literature search was carried out using PubMed, Scopus, Web of Science and Central databases. A total of 1,721 articles were identified, from which nine full-text clinical trials were qualified to enter the current meta-analysis. The assessment groups included patients with type 2 diabetes, and levels of C-peptide, glycosylated hemoglobin and insulin dose were analyzed before and after mesenchymal stem cell infusion. Data analysis was carried out in Stata version 11, and the Jadad Score Scale was applied for quality assessment. Changes in levels of C-peptide after mesenchymal stem cell therapy were: standardized mean difference 0.20, 95% confidence interval -0.61 to 1.00, glycosylated hemoglobin levels were: standardized mean difference -1.45, 95% confidence interval -2.10 to -0.79 and insulin dose were: standardized mean difference -1.40, 95% confidence interval -2.88 to 0.09. This meta-analysis of prospective studies showed associations between mesenchymal stem cell therapy and control of glucose level in patients with type 2 diabetes.


Water-soluble contrast study predicts the need for early surgery in adhesive small bowel obstruction.
The optimal period of conservative treatment for adhesive small bowel obstruction remains controversial. This study sought to determine whether a 24-h abdominal radiograph after oral Urografin is a reliable indicator for operation in patients with adhesive small bowel obstruction. One hundred and sixty-one patients who suffered from adhesive intestinal obstruction without clinical evidence of strangulation or gangrene underwent a Urografin study. Some 40 ml Urografin mixed with 40 ml distilled water was administered either orally or via a nasogastric tube to each patient. Serial plain abdominal radiographs were taken 4, 8, 16 and 24 h later. If an earlier plain radiograph showed that contrast medium had reached the ascending colon, subsequent radiographs were not taken. Contrast medium reached the colon within 24 h in 112 patients (70 per cent). These patients were all treated successfully with non-operative methods. Contrast medium was not observed in the colon within the first 24 h in 49 patients (30 per cent). Operation was performed in 47 of these patients and non-operative treatment was given in two. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of Urografin reaching the colon within 24 h as an indicator for non-operative treatment were 98, 100, 99, 100 and 96 per cent respectively. All patients with evidence of Urografin reaching the colon within 24 h were treated successfully with non-operative methods. The results of this prospective study suggest that patients with adhesive intestinal obstruction in whom contrast medium fails to reach the colon within 24 h should receive prompt surgical intervention.


Localization of mRNA for protein phosphatase 2C in the brain of adult rats.
Type 2C protein phosphatase (PP2C) is one of four major serine-threonine specific phosphoprotein phosphatases which modulate various intracellular activities. By in situ hybridization analysis of the adult rat, expression signals of mRNA for PP2C were observed most highly in the granule cells and Purkinje cells of the cerebellum, the pyramidal cells of the hippocampus and granule cells of the dentate gyrus, and plexus choroideus of the lateral ventricle, whereas moderate levels of its expression were observed in the medial habenula, piriform cortex and the pineal body. Several discrete nuclei of the brainstem including pars compacta of the substantia nigra, the pontine nuclei, and the locus ceruleus expressed the mRNA moderately. Weak expression of PP2C mRNA was observed in mitral and internal granule cells of the olfactory bulb, spinal cord gray matter, the cerebral neocortex, thalamic and hypothalamic nuclei. Only faint expression was detected in the caudate putamen. These patterns of expression are different from that of calcineurin/PP2B reported by other immunohistochemical studies and it is suggested that various neuronal proteins are differentially dephosphorylated by the different types of PP.


Surgical treatment of lone atrial fibrillation by mid-sternotomy Maze procedure under standard cardiopulmonary bypass.
The aim of article is to give a brief description to the surgical strategies for patients with lone atrial fibrillation without associated cardiac operations, and present the possible indications of on-pump Maze procedures through a mid-sternotomy approach.


Altered gut microbiota in hepatocellular carcinoma: Insights into the pathogenic mechanism and preclinical to clinical findings.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. It is usually the result of pre-existing liver damage caused by hepatitis B and/or C virus infection, alcohol consumption, nonalcoholic steatohepatitis (NASH), aflatoxin exposure, liver cirrhosis, obesity, and diabetes. A growing body of evidence suggests that gut microbes have a role in cancer genesis. More research into the microbiome gut-liver axis has recently contributed to understanding how the gut microbiome facilitates liver disease or even HCC progression. This review focuses on the preclinical results of gut-related hepatocarcinogenesis and probiotics, prebiotics, and antibiotics as therapeutic interventions to maintain gut microbial flora and minimize HCC-associated symptoms. Understanding the mechanistic link between the gut microbiota, host, and cancer progression could aid us in elucidating the cancer-related pathways and drive us toward preventing HCC-associated gut microbiota dysbiosis.


Association of Body Mass Index With Incidence and Progression of Knee Effusion on Magnetic Resonance Imaging and on Knee Examination.
To determine the association of body mass index (BMI) with incidence and progression of knee effusion on magnetic resonance imaging (MRI) and physical examination (PE) in a longitudinal cohort with knee pain. A population-based cohort was assessed at baseline and 3 years (n = 163). BMI was categorized as normal (<25), overweight (25-29.9), and obese (≥30). Knee effusion was graded as 0-3 (absent/mild/moderate/severe) on MRI and 0-1 (absent/present) on PE. Progression of MRI effusion (MRIeff ) was an increase of ≥1 grade in those with grade 1 or 2 at baseline. Incident MRIeff and PE effusion (PEeff ) were any effusion at followup (>0) in those with grade 0 at baseline. A second type of incident MRIeff was effusion grade ≥2 at followup in those with grade <2 at baseline. Exponential regression analysis was used, adjusted for age, sex, and radiographic severity. Incident MRIeff ≥1, incident MRIeff ≥2, incident PEeff , and progression of MRIeff were seen in 14 of 73 (19%), 18 of 140 (13%), 26 of 127 (20%), and 18 of 86 (21%), respectively. There was a borderline statistical association of obesity with progression of MRIeff (hazard ratio [HR] 3.3 [95% confidence interval (95% CI) 1.0-11.2]) and with incident MRIeff ≥2 (HR 3.4 [95% CI 1.0-11.5]). BMI was not associated with incident MRIeff ≥1 (HR overweight 1.1 [95% CI 0.3-3.6], obese 1.0 [95% CI 0.2-5.0]). Overweight was associated with incident PEeff (HR 4.5 [95% CI 1.4-14.2]), while obesity was not statistically significant (HR 3.1 [95% CI 0.9-11.1]). Obesity was a risk factor for incident and progressive knee effusion in this population-based cohort. These findings highlight an important link between obesity and inflammation in knee osteoarthritis.


Clinical and Laboratory Characteristics of a Tinea Capitis Outbreak Among Novice Buddhist Monks.
Sixty novice Buddhist monks with tinea capitis confirmed according to clinical presentation and mycological laboratory finding were included in this study. Mixed-type clinical presentation was observed in approximately half of all cases, together with scarring alopecia (95%) and superficial fungal skin infection at locations other than the scalp (43.3%). The major isolated organism was Trichophyton violaceum, and mixed-organism infection was found in 27 cases (45%). Slow-onset presentation and an extensive area of infection were significantly associated with mixed-type clinical presentation.


Effects of stress on leukocyte trafficking and immune responses: implications for vaccination.
Increased susceptibility of animals to infectious disease during the periparturient period results in suffering and economic losses. Stress appears to delay inflammation by reducing efficiency of CD62L-mediated immune surveillance by phagocytes. It is important to note that the effects of stress are not limited to alteration of leukocyte trafficking patterns since various stressors (e.g., transport, parturition, and castration) also decrease IFN-gamma secretion by lymphocytes, and may decrease antigen presentation efficiency by down-regulating class II molecule expression on antigen presenting cells, and delay or impair immune responses to vaccination. Documented immunosuppression in periparturient animals, particularly the bias toward Th2 immune responses, and also changes in general leukocyte trafficking patterns suggest that vaccination intending to elicit cell-mediated immunity may not be efficacious at this point of the production cycle. Based on findings of numerous periparturient studies on immunosuppression in cattle, waiting at least 30 days after parturition before administering routine vaccinations is recommended.


Acute meal-induced changes in hepatic glycerolipid metabolism are unimpaired in severely diabetic rats: implications for the role of insulin.
The effect of food intake on the partitioning of diacylglycerol between phospholipid and triacylglycerol synthesis, and on the fractional rate of secretion of triacylglycerol was studied in starved-refed diabetic rats by using the technique of selective labelling of hepatic fatty acids in vivo. Acute and phasic responses in these parameters similar to those observed previously in normal animals were obtained, in spite of the absence of any insulin response to refeeding. Labelling of the major phospholipids (phosphatidylcholine and phosphatidylethanolamine) increased markedly at the expense of triacylglycerol labelling. In addition, the fractional rate of secretion of newly-labelled triacylglycerol was decreased. The data suggest that insulin is not obligatorily involved in any decrease in hepatic triacylglycerol secretion in the prandial period, but that it may act synergistically with other meal-induced signals to mediate this effect in normal animals.


A non-invasive imaging for the in vivo tracking of high-speed vesicle transport in mouse neutrophils.
Neutrophils play an essential role in the innate immune response. To understand neutrophil activity, the development of a new technique to observe neutrophils in situ is required. Here, we report the development of a non-invasive technique for the in vivo imaging of neutrophils labeled with quantum dots, up to 100 μm below the skin surface of mice. Upon inflammation neutrophils began to extravasate from blood vessels and locomoted in interstitial space. Most intriguingly, the quantum dots were endocytosed into vesicles in the neutrophils, allowing us to track the vesicles at 12.5 msec/frame with 15-24 nm accuracy. The vesicles containing quantum dots moved as "diffuse-and-go" manner and were transported at higher speed than the in vitro velocity of a molecular motor such as kinesin or dynein. This is the first report in which non-invasive techniques have been used to visualize the internal dynamics of neutrophils.


Anti-inflammatory effects of propofol are mediated by apolipoprotein M in a hepatocyte nuclear factor-1α-dependent manner.
Propofol (2,6-diisopropylphenol) is probably the most widely used intravenous hypnotic agent in daily practice. However, its anti-inflammatory properties have seldom been addressed. In this study, we evaluated the anti-inflammatory activity and mechanisms of propofol on lipopolysaccharide (LPS)-induced inflammation in vivo and in vitro and found that propofol markedly inhibited LPS-induced production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, and expression of inducible nitric oxide synthase (iNOS). At the same time, the expression of hepatocyte nuclear factor-1α (HNF-1α) and apolipoprotein M (APOM) was inhibited by treatment with LPS and LPS-induced down-regulation of HNF-1α expression and APOM expression could be compensated by propofol treatment. However, propofol could not compensate LPS-induced down-regulation of APOM expression by treatment with HNF-1α siRNA and the suppressive effect on LPS-induced pro-inflammatory cytokines production by propofol was significantly compensated by treatment with APOM siRNA. These results provide evidence that propofol may first up-regulate APOM expression by enhancing HNF-1α expression and then inhibit pro-inflammatory cytokine production in LPS-stimulated cells. Therefore, our study may be useful in understanding the critical effect of propofol in patients with systemic inflammatory response syndrome.


Predictors of methadone program non-retention for opioid analgesic dependent patients.
This study evaluates loss to follow-up in a methadone maintenance treatment (MMT) program for patients dependent on opioid analgesics in a community in eastern Canada. Data were collected using the Addiction Severity Index Lite. The probability of loss to follow-up was evaluated using a time-to-event analysis. Involuntary and voluntary program discharges were treated separately as the outcomes of interest. Multivariate Cox proportional hazards models were used to explore the role of various patient-related attributes. The probabilities of involuntary and voluntary discharges at 1 year were 20% and 14%, respectively. In this exploratory analysis, determinants of loss to follow-up were characteristics related to drug use history (e.g., use of sedatives) and its consequences (e.g., number of lifetime arrests), and differed for each outcome. Some determinants of involuntary discharge were modified by sex. Understanding predictors of specific loss to follow-up outcomes may help MMT programs improve patient retention.


Specific contribution of estrogen receptors on mitogen-activated protein kinase pathways and vascular cell activation.
Randomized clinical trials have not provided conclusive data that hormone replacement therapy confers cardioprotection against coronary artery disease in postmenopausal women. However, other studies have shown that estrogens can induce beneficial effects on the vasculature. Nevertheless, the specific contribution of estrogen receptors (ERs) alpha and beta on vascular cells is not well characterized. Therefore, we used an antisense gene therapy approach to investigate the contribution of ERalpha and ERbeta on p38 and p42/44 mitogen-activated protein kinase (MAPK) activation and on vascular cell responsiveness. Treatment of porcine smooth muscle cells (PSMCs) with platelet-derived growth factor-BB induced p38 and p42/44 MAPK activation and their migration and proliferation. These effects were prevented by pretreatment with 17beta-estradiol (17betaE). The inhibitory effects of 17betaE on PSMCs were abrogated by the downregulation of ERbeta protein expression with selective ERbeta mRNA antisense oligomers, whereas the downregulation of ERalpha had no effect. However, treatment of porcine aortic endothelial cells with 17betaE promoted p38 and p42/44 MAPK phosphorylation and their migration and proliferation. These effects were ERalpha dependent, as defined by antisense gene therapy. These results suggest that in PSMCs, 17betaE reduces p42/44 and p38 MAPK activity through ERbeta stimulation, whereas in contrast, in porcine aortic endothelial cells, 17betaE induces p42/44 and p38 MAPK through ERalpha activation. 17betaE may contribute to the vascular healing process and to the prevention of restenosis by improving reendothelialization through ERalpha activation and by decreasing smooth muscle cell migration and proliferation through ERbeta stimulation.


Resolution and reconstitution of cytochrome P-450 containing steroid hydroxylation system of Rhizopus nigricans.
11 alpha-hydroxylation of progesterone in the eucaryotic filamentous fungus Rhizopus nigricans is catalyzed by a monooxygenase. Three components of this multienzyme system, cytochrome P-450, rhizoporedoxin and a FAD containing rhizoporedoxin reductase have been separated from the postmitochondrial fraction on DEAE cellulose. Using NADPH as electron donor we showed that the presence of all three components was necessary for the reconstitution of the active electron transport chain.


Progress in the Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease.
Pulmonary hypertension, frequently complicating the course of patients with fibrotic interstitial lung disease, is associated with significantly increased morbidity and mortality. The availability of multiple medications to treat pulmonary arterial hypertension has resulted in these agents being used beyond their original indication, including in patients with interstitial lung disease. Whether pulmonary hypertension in the context of interstitial lung disease is an adaptive response not to be treated or a maladaptive phenomenon amenable to therapy has been uncertain. Although some studies have suggested a benefit of treatment, there have been others demonstrating harm. This concise clinical review provides an overview of prior studies and the issues that have plagued drug development for a patient population in dire need of treatment options. More recently, there has been a paradigm shift, with the largest study to date demonstrating benefit, resulting in the first approved therapy in the United States for patients with interstitial lung disease complicated by pulmonary hypertension. A pragmatic management algorithm in the context of changing definitions, comorbid contributors, and an available treatment option is provided, as are considerations for future clinical trials.


Photosynthetic recovery of the resurrection plant Selaginella lepidophylla (Hook. and Grev.) Spring: effects of prior desiccation rate and mechanisms of desiccation damage.
The effects of desiccation rate on photosynthetic recovery of the resurrection plant Selaginella lepidophylla (Hook. and Grev.) Spring were examined. Gas exchange over a 24 h rehydration period, ribulose bisphosphate carboxylase conservation in desiccated fronds, de novo protein synthesis rate during rehydration, and frond leakage rate during rehydration were measured following desiccation at various rates. Seven-day hydrated, fully recovered plants were dried at four rates. The initial decline in tissue fresh weight/dry weight ratio was essentially linear to a ratio value of 1.35, the point at which frond curling occurred, but slowed thereafter. Frond curling required 5.5, 52, 94, and 175 h of desiccation, respectively, for the four treatments.The rate of net photosynthesis after 24 h of rehydration was greatest for the two intermediate drying speeds; both very rapid and very slow drying were associated with significantly reduced rates. Electrolyte leakage was greatest following very rapid drying and de novo protein synthesis was impaired following very slow drying. Ribulose bisphosphate carboxylase conservation was not significantly affected by drying speed. These results support the hypothesis that desiccation injury is multicausal and that specific components of the photosynthetic recovery process respond differently to desiccation rate. However, in spite of these significant desiccation rate effects, overall photosynthetic recovery in S. lepidophylla appears to be relatively tolerant of widely varying rates of desiccation.


[Experimental studies of the pathomechanism of portal encephalopathy. II. Monoamine oxidase (MAO) activity in the rat brain after porta- caval shunt using 2 different methods].
The authors present effect of the end to side portacaval shunt (E-S PCS) and side to side portacaval shunt (S-S PCS) on monoamine oxidase (MAO) activity in brain cortex and cerebellum of rats. There were significant differences between two experimental models of PCS. Our results show greater increase in MAO activity after end to side portacaval shunt.


System, crowd, and communal innovation: can the monks solve the elephant?
A systems approach reveals emergent group behavior of an assembly of interacting elements, networks, and subgroups, using modeling and simulation analyses that are capable of handling massive data and complex structures. As system complexity and data sizes increase, efficient collaboration becomes crucial to construct, refine, and analyze the model in a timely manner. A solution may be "crowd sourcing," which provides a platform for communal innovation.


Antimicrobial and cytotoxic activity of hypochlorous acid: interactions with taurine and nitrite.
HOCl, a major bactericidal product of neutrophil MPO-halide system reacts with taurine to form taurine chloramine (TauCl), a less toxic anti-inflammatory mediator. Recently, it has been reported that HOCl may also react with nitrite (NO2-), a major end-product of nitric oxide (NO) metabolism, to form very active oxidant, nitryl chloride (NO2Cl). The present study was conducted to elucidate the effect of nitrite on bactericidal and some immunoregulatory properties of HOCl and TauCl. TauCl was prepared from NaOCl and taurine. The reaction was carried out at pH 5.0 and pH 7.4, in the presence or absence of nitrite. All reactions were monitored by UV absorption spectra. Bactericidal activity of HOCl and TauCl in the presence of nitrite was tested by incubation of E. coli with the compounds and determined by the pour-plate method. To test the effect of the compounds on activity of inflammatory cells, murine peritoneal neutrophils (PMN) and macrophages were used. The cells were activated in vitro with either LPS, IFN-gamma or zymosan and the production of following mediators was measured: reactive oxygen species using luminol-dependent chemiluminescence; nitric oxide by Griess reaction; TNF-alpha using capture ELISA. In addition, we tested the effect of HOCl and TauCl on activity of myeloperoxidase (MPO). At physiological pH nitrite reacts with HOCl but not with TauCl. This reaction was abolished in the presence of taurine. Nitrite prevented HOCl-mediated bacterial killing, inhibition of MPO activity, cellular cytotoxicity and inhibition of TNF-alpha production. Nitrite did not affect any activity of TauCl. We have shown that nitrite may react in vitro with HOCl but not with TauCl, to form new biologically active product(s). We did not confirm the hypothesis that a product of HOCl reaction with nitrite is more toxic than HOCl. To the contrary, we found that nitrite diminished bactericidal and immunoregulatory properties of HOCl. In vivo, nitrite will also compete with taurine for reaction with PMN-released HOCl. Nevertheless, due to high concentration of taurine in PMN cytosol, formation of TauCl will be a major regulatory mechanism of MPO-halide-system.


Defective glomerular [3H]lysoPAF metabolism in the autologous phase of rabbit nephrotoxic nephritis.
Glomerular infiltration of blood-derived mononuclear cells contributes to the glomerular injury in the autologous phase of nephrotoxic nephritis (NTN). LysoPAF has recently been shown to be chemotactic for human monocytes, thus its accumulation might account for monocyte recruitment. We investigated [3H]lysoPAF metabolism in isolated glomeruli from normal and NTN rabbits studied both in the heterologous and in the autologous phases of the disease. [3H]lysoPAF was converted to [3H]1-O-alkyl-glycerol and [3H]1-O-alkyl-2-acyl-GPC by phospholipase C and acyltransferase, respectively, both in normal and NTN glomeruli. Glomerular metabolism of [3H]lysoPAF was normal during the heterologous phase of NTN. By contrast, in isolated glomeruli from NTN rabbits studied in the autologous phase of the disease, a significantly lower [3H]lysoPAF degradation occurred with respect to normal ones. This defective degradation resulted in a significantly reduced formation of [3H]1-O-alkyl-glycerol. The apparent Km for enzymatic conversion of [3H]lysoPAF to [3H]1-O-alkyl-glycerol, determined at 15 minutes as a function of [3H]lysoPAF concentration, was doubled in glomeruli from rabbits studied in the autologous phase of NTN as compared to normal ones, while Vmax values were similar in the two groups. These results show a defective glomerular lysoPAF degradation in the autologous phase of NTN, likely due to a decreased affinity of phospholipase C to lysoPAF. Altered lysoPAF metabolism results in glomerular accumulation of lysoPAF in the autologous phase of NTN, as shown by significantly higher levels of lysoPAF measured in nephritic glomeruli as compared to normal ones.


The molecular structure of the phosphate mineral chalcosiderite--a vibrational spectroscopic study.
The mineral chalcosiderite with formula CuFe6(PO4)4(OH)8·4H2O has been studied by Raman spectroscopy and by infrared spectroscopy. A comparison of the chalcosiderite spectra is made with the spectra of turquoise. The spectra of the mineral samples are very similar in the 1200-900 cm(-1) region but strong differences are observed in the 900-100 cm(-1) region. The effect of substitution of Fe for Al in chalcosiderite shifts the bands to lower wavenumbers. Factor group analysis (FGA) implies four OH stretching vibrations for both the water and hydroxyl units. Two bands ascribed to water are observed at 3276 and 3072 cm(-1). Three hydroxyl stretching vibrations are observed. Calculations using a Libowitzky type formula show that the hydrogen bond distances of the water molecules are 2.745 and 2.812 Å which are considerably shorter than the values for the hydroxyl units 2.896, 2.917 and 2.978 Å. Two phosphate stretching vibrations at 1042 and 1062 cm(-1) in line with the two independent phosphate units in the structure of chalcosiderite. Three bands are observed at 1102, 1159 and 1194 cm(-1) assigned to the phosphate antisymmetric stretching vibrations. FGA predicts six bands but only three are observed due to accidental degeneracy. Both the ν2 and ν4 bending regions are complex. Four Raman bands observed at 536, 580, 598 and 636 cm(-1) are assigned to the ν4 bending modes. Raman bands at 415, 420, 475 and 484 cm(-1)are assigned to the phosphate ν2 bending modes. Vibrational spectroscopy enables aspects of the molecular structure of chalcosiderite to be assessed.


Social dynamics within decomposer communities lead to nitrogen retention and organic matter build-up in soils.
The chemical structure of organic matter has been shown to be only marginally important for its decomposability by microorganisms. The question of why organic matter does accumulate in the face of powerful microbial degraders is thus key for understanding terrestrial carbon and nitrogen cycling. Here we demonstrate, based on an individual-based microbial community model, that social dynamics among microbes producing extracellular enzymes ('decomposers') and microbes exploiting the catalytic activities of others ('cheaters') regulate organic matter turnover. We show that the presence of cheaters increases nitrogen retention and organic matter build-up by downregulating the ratio of extracellular enzymes to total microbial biomass, allowing nitrogen-rich microbial necromass to accumulate. Moreover, increasing catalytic efficiencies of enzymes are outbalanced by a strong negative feedback on enzyme producers, leading to less enzymes being produced at the community level. Our results thus reveal a possible control mechanism that may buffer soil CO2 emissions in a future climate.


Safety of Natalizumab infusion in multiple sclerosis patients during active SARS-CoV-2 infection.
COVID-19 pandemic represented a challenge in the management of treatments for Multiple Sclerosis (MS), such as Natalizumab (NTZ). NTZ interferes with the homing of lymphocytes into the central nervous system, reducing immune surveillance against opportunistic infection. Although NTZ efficacy starts to decline 8 weeks after the last infusion, increasing the risk of disease reactivation, evidence is lacking on the safety of reinfusion during active SARS-CoV-2 infection. We report clinical outcomes of 18 pwMS receiving NTZ retreatment during confirmed SARS-CoV-2 infection. No worsening of infection or recovery delay was observed. Our data supports the safety of NTZ redosing in these circumstances.


Decreased Alpha Reactivity from Eyes-Closed to Eyes-Open in Non-Demented Older Adults with Alzheimer's Disease: A Combined EEG and [18F]florbetaben PET Study.
The degree of alpha attenuation from eyes-closed (EC) to eyes-open (EO) has been suggested as a neural marker of cognitive health, and its disruption has been reported in patients with clinically defined Alzheimer's disease (AD) dementia. We tested if EC-to-EO alpha reactivity was related to cerebral amyloid-β (Aβ) deposition during the early stage of AD. Non-demented participants aged ≥55 years who visited the memory clinic between March 2018 and June 2019 (N = 143; 67.8% female; mean age±standard deviation, 74.0±7.6 years) were included in the analyses. Based on the [18F]florbetaben positron emission tomography assessment, the participants were divided into Aβ+ (N = 70) and Aβ- (N = 73) groups. EEG was recorded during the 7 min EC condition followed by a 3 min EO phase, and a Fourier transform spectral analysis was performed. A significant three-way interaction was detected among Aβ positivity, eye condition, and the laterality factor on alpha-band power after adjusting for age, sex, educational years, global cognition, depression, medication use, and white matter hyperintensities on magnetic resonance imaging (F = 5.987, p = 0.016); EC-to-EO alpha reactivity in the left hemisphere was significantly reduced in Aβ+ subjects without dementia compared with the others (F = 3.984, p = 0.048). Among mild cognitive impairment subjects, alpha reactivity additively contributed to predict cerebral Aβ positivity beyond the clinical predictors, including vascular risks, impaired memory function, and apolipoprotein E ɛ4. These findings support that EC-to-EO alpha reactivity acts as an early biomarker of cerebral Aβ deposition and is a useful measurement for screening early-stage AD.


Influence of salinity on the toxicity of copper and cadmium to Zebrafish embryos.
Salinization has become a serious worldwide environmental perturbation in freshwater ecosystems. Concomitantly, many of such ecosystems are already impacted by other toxicants, which together with increased salinity may result in synergistic, antagonistic or additive toxic effects to biota. This work intended to assess the influence of increasing salinity (by using NaCl) on the lethal and sublethal toxicity of two metallic elements (copper and cadmium) in embryos of the fish species Danio rerio. This goal was achieved by exposing zebrafish embryos to seven concentrations of NaCl, individually or combined with each metal, using a full factorial design. The following endpoints were monitored in the test organisms: mortality, hatching, malformations and the enzymatic activity of glutathione S-transferase (GST) and cholinesterase (ChE). Overall, moderate salinity levels alleviated the lethal toxicity of both copper and cadmium although this effect was stronger in the copper assay. This effect was also influenced, as expected, by the concentrations of the metals indicating that the protective effect of salt only reaches some levels, after what is overwhelmed by the high metal toxicity, especially with the non-essential metal cadmium. At sub-lethal concentrations, the interactive effect resulting from NaCl and metals was not consistent and varied with the endpoint analyzed and the metal tested. Overall, the interactions between the salt and metals seem complex and with more drastic effects (positive or negative) on lethal endpoints than sub-lethal.


Nicotinamide adenine dinucleotide phosphate-malic enzyme of rat liver. Purification, properties, and immunochemical studies.
Rat liver malic enzyme (EC 184.108.40.206) was purified from livers of rats fasted and refed a high sucrose diet containing 1% desiccated thyroid powder. The purification was accomplished by a six-step procedure. The specific activity of the purified enzyme was increased 181-fold above that of the initial high speed supernatant of liver extracts. Slight additional purification of malic enzyme was achieved with preparative disc electrophoresis. The specific activities of the purified rat liver malic enzyme from the least two steps were between 28.0 and 30.5 units per mg of protein. Homogeneity of the purified enzyme was determined by disc and starch gel electrophoresis as well as sedimentation velocity and sedimentation equilibrium studies. The molecular weight and S20, w values of rat liver malic enzyme are 268,000 and 10.2, respectively. Amino acid analysis based on milligram of protein hydrolyzed yielded higher amounts of leucine and glutamic acid but lower quantities of alanine and voline per subunit than the corresponding Escherichia coli enzyme...


Magnetic Resonance Imaging Combined With Second-look Ultrasonography in Predicting Pathologic Complete Response After Neoadjuvant Chemotherapy in Primary Breast Cancer Patients.
Magnetic resonance imaging (MRI) or ultrasonography (US) alone is limited in the ability to predict the pathologic complete response (pCR) accurately after neoadjuvant chemotherapy (NAC). The aim of the present study was to predict the pCR using MRI combined with second-look US in primary breast cancer patients. A total of 1274 consecutive primary breast cancer patients who were examined by MRI and second-look US before and after NAC and had undergone breast-conserving surgery from 2004 to 2014 were included. The positive predictive value (PPV) of a clinical complete response (cCR) by MRI alone and MRI plus US was assessed. A CR was defined as no residual invasive carcinoma. The presence of a residual in situ component was also assessed (ypTis). Of the 1274 patients, 333 (26.1%) had a pCR (ypT0/is), and 102 (8.0%) had a residual in situ component (ypTis). A cCR was found in 247 patients (19.4%) using MRI alone and in 182 patients (14.3%) using MRI plus US. The PPV for a cCR using MRI alone was 79.4% and the PPV for MRI plus US was 86.8%. The PPV for a cCR by MRI plus US was the greatest at 98.1% in the estrogen receptor-negative (ER-)/human epidermal growth factor receptor-positive (HER2+) group (86.5% in the ER+/HER2+, 83.0% in the ER-/HER2-, and 64.7% in the ER+/HER2- groups). The PPV for residual in situ component was as low as 72.2%. Our results have shown that MRI combined with second-look US in predicting for a pCR was useful compared with MRI alone, especially for ER-/HER2+. However, it was difficult to predict for the presence of a residual in situ component. Our ongoing prospective multi-institutional study has shown that adding vacuum-assisted biopsy to MRI plus second-look US is warranted to improve the prediction of pCR for omitting breast surgery.


Intervertebral disc regeneration using platelet‑rich plasma‑containing bone marrow‑derived mesenchymal stem cells: A preliminary investigation.
Platelet‑rich plasma (PRP) is a promising strategy for intervertebral disc degeneration (IDD). However, the short half‑life of growth factors released from PRP cannot continuously stimulate the degenerated discs. Thus, the present study hypothesized that the combined use of PRP and bone marrow‑derived mesenchymal stem cells (BMSCs) may repair the early degenerated discs in the long term for their synergistic reparative effect. In the present study, following the induction of early IDD by annular puncture in rabbits, PRP was prepared and mixed with BMSCs (PRP‑BMSC group) for injection into the early degenerated discs. As controls, phosphate‑buffered saline (PBS; PBS group) and PRP (PRP group) were similarly injected. Rabbits without any intervention served as a control group. At 8 weeks following treatment, histological changes of the injected discs were assessed. Magnetic resonance imaging (MRI) was used to detect the T2‑weighted signal intensity of the targeted discs at weeks 1, 2 and 8 following treatment. Annular puncture resulted in disc narrowing and decreased T2‑weighted signal intensity. At weeks 1 and 3, MRI examinations showed regenerative changes in the PRP‑BMSC group and PRP group, whereas the PBS group exhibited a continuous degenerative process of the discs. At 8 weeks post‑injection, the PRP‑BMSCs induced a statistically significant restoration of discs, as shown by MRI (PRP‑BMSCs, vs.PRP and PBS; P<0.05), which was also confirmed by histological evaluations. Thus, compared with PRP, the administration of PRP‑containing BMSCs resulted in a superior regenerative effect on the early degenerated discs, which may be a promising therapeutic strategy for the restoration of early degenerated discs.


Genetic and Phenotypic Analysis of Ovule Development in Arabidopsis.
The plant seed is a remarkable structure that represents the single most important energy source in global diets. The stages of reproductive growth preceding seed formation are particularly important since they influence the number, size, and quality of seed produced. The progenitor of the seed is the ovule, a multicellular organ that produces a female gametophyte while maintaining a range of somatic ovule cells to protect the seed and ensure it receives maternal nourishment. Ovule development has been well characterized in Arabidopsis using a range of molecular, genetic, and cytological assays. These can provide insight into the mechanistic basis for ovule development, and opportunities to explore its evolutionary conservation. In this chapter, we describe some of these methods and tools that can be used to investigate early ovule development and cell differentiation.


mHealth Physical Activity Intervention for Individuals With Spinal Cord Injury: Planning and Development Processes.
Interventions to support physical activity participation among individuals with spinal cord injury (SCI) are required given this population's low levels of physical activity and extensive barriers to quality physical activity experiences. This study aimed to develop a mobile health intervention, called SCI Step Together, to improve the quantity and quality of physical activity among individuals with SCI who walk. Our overarching methodological framework was the Person-Based approach. This included the following 4 steps: conduct primary and secondary research (step 1); design intervention objectives and features (step 2a); conduct behavioral analysis and theory (step 2b); create a logic model (step 3); and complete the SCI Step Together program content and integrated knowledge translation (IKT; step 4), which occurred throughout development. The partnership approach was informed by the SCI IKT Guiding Principles. Three end users pilot-tested the app and participated in the interviews. Step 1 identified issues to be addressed when designing intervention objectives and features (step 2a) and features were mapped onto the Behavior Change Wheel (step 2b) to determine the behavior change techniques (eg, action planning) to be included in the app. The logic model linked the mechanisms of action to self-determination theory (steps 2/3). Interviews with end users generated recommendations for the technology (eg, comparing physical activity levels with guidelines), trial (eg, emailing participants' worksheets), and intervention content (eg, removing graded tasks; step 4). Using the SCI IKT Guiding Principles to guide partner engagement and involvement ensured that design partners had shared decision-making power in intervention development. Equal decision-making power maximizes the meaningfulness of the app for end users. Future research will include testing the acceptability, feasibility, and engagement of the program. Partners will be involved throughout the research process. ClinicalTrials.gov: NCT05063617; https://clinicaltrials.gov/ct2/show/NCT05063617.


Gastric microvascular endothelium: a major target for aspirin-induced injury and arachidonic acid protection. An ultrastructural analysis in the rat.
Exposure of the gastric mucosa to aspirin results in exfoliation of the surface epithelium and deep mucosal necrosis. We assessed the changes in the mucosal microvessels during aspirin-induced injury and arachidonic acid protection of the gastric mucosa using transmission electron microscopy. Male Sprague-Dawley rats received intragastric pretreatment with either solubilizer (control) or detergent solubilized arachidonic acid (148 mg kg-1). One hour later 1-ml suspension of 200 mg kg-1 body weight acidified aspirin was administered intragastrically. The ultrastructure of mucosal microvasculature was assessed at 15 min and 4 h after aspirin administration both qualitatively and quantitatively by determining the number of necrotic or damaged capillaries in standardized mucosal sections. In addition, mucosal specimens were immunostained with a specific antiserum against vimentin, an endothelial marker, and fluorescence intensity was measured with a Nikon FX microscopic photometric system. In control rats, aspirin produced significant damage to both superficial and deeper microvessels consisting of: rupture of capillary walls, necrosis of endothelial cells, damage to endothelial organelles, deposition of fibrin and adherence of platelets to damaged endothelium. Vimentin fluorescence was reduced three-fold. Microvascular injury preceded the development of deep necrotic lesions. Microvascular damage and deep mucosal necrosis were significantly reduced by arachidonic acid pretreatment. We conclude that gastric mucosal microvessels are the major target for aspirin-induced injury and arachidonic acid protection.


Binding kinetics of cariprazine and aripiprazole at the dopamine D3 receptor.
The dissociation behaviours of aripiprazole and cariprazine at the human D2 and D3 receptor are evaluated. A potential correlation between kinetics and in vivo profiles, especially cariprazine's action on negative symptoms in schizophrenia, is investigated. The binding kinetics of four ligands were indirectly evaluated. After the receptor preparations were pre-incubated with the unlabelled ligands, the dissociation was initiated with an excess of [3H]spiperone. Slow dissociation kinetics characterizes aripiprazole and cariprazine at the D2 receptor. At the D3 receptor, aripiprazole exhibits a slow monophasic dissociation, while cariprazine displays a rapid biphasic behaviour. Functional ß-arrestin assays and molecular dynamics simulations at the D3 receptor confirm a biphasic binding behaviour of cariprazine. This may influence its in vivo action, as the partial agonist could react rapidly to variations in the dopamine levels of schizophrenic patients and the ligand will not quantitatively dissociate from the receptor in one single step. With these findings novel agents may be developed that display rapid, biphasic dissociation from the D3R to further investigate this effect on in vivo profiles.


The synthesis of a series of deoxygenated 2,3-difluoro-N-acteylneuraminic acid derivatives as potential sialidase inhibitors.
Here we describe the successful syntheses of a series of 4-, 7-, 8- and 9-deoxygenated 2,3-difluoro-N-acetylneuraminic acid derivatives as potential mechanism-based inhibitors of sialidases. The syntheses commenced utilising an enzyme-catalysed aldolase reaction between N-acetyl mannosamine and β-fluoropyruvic acid to give 3-fluoro-N-acetyl-neuraminic acid. This common intermediate was then used in selective protection protocols and Barton-McCombie deoxygenations to generate the complete set of mono-deoxygenated 3-fluoro-N-acetylneuraminic acid derivatives. Finally, a fluorination step utilising (diethylamino)sulfur trifluoride (DAST) was used to successfully generate each of the target difluorides.


Femtosecond laser-assisted cataract surgery in patients with phakic intraocular lenses and low endothelial cell counts: a case report.
Phakic intraocular lens (PIOL) implantation has been used to correct myopia and myopic astigmatism, although corneal decompensation can occur after implantation. Femtosecond laser-assisted cataract surgery (FLACS) has gained in popularity due to its lower postoperative astigmatism and endothelial loss. Herein, we report the use of FLACS in patients who previously received PIOL implantation and have a low corneal endothelial cell count. Two patients with a previous iris-claw PIOL implantation were enrolled. The preoperative corrected distance visual acuity (CDVA) and diopter sphere (DS) were 20/32 and -0.25 D in patient 1 and 20/32 and -3.00 D in patient 2. Specular microscope examination revealed an endothelial cell density (ECD) of 1532/mm2 in patient 1 and 1620/mm2 in patient 2. Capsulotomy was performed smoothly using a femtosecond laser. Postoperative CDVA improved in both eyes, with a difference of DS less than 1 D from the preoperative estimation. Specular microscope examination revealed a decreased endothelial cell density (ECD) in patient 2, but no signs of corneal decompensation were detected. The influence of using PIOL on capsulotomies performed via FLACS, in combination with preoperative refraction calculation, is minimal. A mild decrease in ECD may occur, but there is a low probability of severe corneal decompensation, even in patients with a low endothelial cell count.


Association between brachial-ankle pulse wave velocity and microvascular complications in type 2 diabetes mellitus.
To investigate the relationship between brachial-ankle pulse wave velocity (baPWV) and microvascular complications in type 2 diabetes mellitus (T2DM). From 2019 to 2021, our hospital enrolled 322 patients with T2DM. Clinical information and biochemical indicators of patients were collected from the inpatient electronic medical record system and analyzed retrospectively. Fundus photography, nerve conduction testing, and sensory threshold measurement were all conducted on the subjects. We measured the pulse wave velocity on both sides of the arm and ankle, then averaged the results. The enrolled cases were divided into two groups based on the baPWV: Group 1 (<the reference cutoff value, n = 160) and Group 2 (≥ the reference cutoff value, n = 162). The association between associated factors and baPWV abnormalities was investigated using a logistic regression model. Group 2 had higher Systolic Blood Pressure(SBP), Diastolic Blood Pressure (DBP), duration of diabetes, Fasting Plasma Glucose (FPG), Blood Urea Nitrogen (BUN) and Serum Uric Acid (SUA) than group 1 (all p < 0.05). The prevalence of diabetic retinopathy, peripheral neuropathy and nephropathy in group 2 was higher compared to group 1 (p < 0.05). After classifying subjects according to the presence or absence of diabetic complications, we found that the baPWV of the Diabetic Peripheral Neuropathy (DPN) group and Diabetic Nephropathy (DN) group was noticeably higher than that of non-DPN group and non-DN group, respectively (both p < 0.05). The baPWV increased with the aggravation of Diabetic Retinopathy (DR) (p < 0.05). Multivariate logistic regression analysis showed that DBP (OR 1.039, 95%CI 1.010-1.068 p = 0.008), duration of diabetes (OR 1.059, 95%CI 1.017-1.103 p = 0.006), FPG (OR 1.104, 95%CI 1.025-1.188 p = 0.009) and BUN (OR 1.128, 95%CI 1.001-1.270 p = 0.048) were all independently and positively associated with baPWV. The baPWV is strongly associated with microvascular complications of T2DM. The DBP, duration of diabetes, FPG, and BUN were all independent associated factors of baPWV.