Summer rainfall over the southwestern Tibetan Plateau controlled by deep convection over the Indian subcontinent.
Despite the importance of precipitation and moisture transport over the Tibetan Plateau for glacier mass balance, river runoff and local ecology, changes in these quantities remain highly uncertain and poorly understood. Here we use observational data and model simulations to explore the close relationship between summer rainfall variability over the southwestern Tibetan Plateau (SWTP) and that over central-eastern India (CEI), which exists despite the separation of these two regions by the Himalayas. We show that this relationship is maintained primarily by 'up-and-over' moisture transport, in which hydrometeors and moisture are lifted by convective storms over CEI and the Himalayan foothills and then swept over the SWTP by the mid-tropospheric circulation, rather than by upslope flow over the Himalayas. Sensitivity simulations confirm the importance of up-and-over transport at event scales, and an objective storm classification indicates that this pathway accounts for approximately half of total summer rainfall over the SWTP.


Giant aneurysm of aortocoronary saphenous vein graft compressing the left pulmonary artery.
This is a case report of a 78-year-old patient with a 7-cm aneurysm of the saphenous vein graft that was used 17 years before to perform a coronary artery bypass grafting on the circumflex artery. CT scan displayed a mass with an internal lumen compressing the left atrium as well as the left pulmonary artery.


Determinants of uptake of intermittent preventive treatment during pregnancy: a review.
Malaria in pregnancy (MiP) contributes to devastating maternal and neonatal outcomes. Coverage of intermittent preventive treatment during pregnancy (IPTp) remains alarmingly low. Data was compiled from MiP programme reviews and performed a literature search on access to and determinants of IPTp. National malaria control and reproductive health (RH) policies may be discordant. Integration may improve coverage. Medication stock-outs are a persistent problem. Quality improvement programmes are often not standardized. Capacity building varies across countries. Community engagement efforts primarily focus on promotion of services. The majority of challenges can be addressed at country level to improve IPTp coverage.


Biocomparison of Three Formulations of the S1P1 Receptor Modulator Ponesimod in Healthy Subjects.
Ponesimod is a potent selective sphingosine-1-phosphate receptor 1 (S1P1) modulator, which leads to a reduction in circulating lymphocytes, reflecting their sequestration within lymphoid organs. Modulation of the S1P1 receptor has been previously described to be an effective treatment of autoimmune diseases (e.g., multiple sclerosis). The aim of this study was to compare the relative bioavailability of two polymorphic forms of ponesimod in capsules (Form A versus Form C; Study 1) and the relative bioavailability of a capsule formulation and a tablet formulation (both polymorphic Form C; Study 2). Two open-label, randomized, two-way crossover studies in healthy subjects were performed. In Study 1, 12 male subjects received a single dose of 20 mg of polymorphic Form A or Form C of ponesimod in a capsule. In Study 2, 14 male and female subjects (ratio 1:1) received a single dose of 40 mg of polymorphic Form C of ponesimod in either a capsule or a tablet formulation. Pharmacokinetic and safety variables (clinical laboratory test results, vital signs, and an electrocardiogram) were assessed. Comparison of the exposure to ponesimod following administration of the formulations in Study 1 showed that the 90 % confidence intervals of the geometric mean ratios for the area under the curve from time zero to infinity (AUC0-inf), the area under the curve from time zero to the time of the last measurable concentration (AUC0-t), the terminal half-life (t ½), and the maximum plasma concentration (C max) were all within the 0.80-1.25 bioequivalence interval. In Study 2, more rapid absorption of ponesimod was observed from the tablet formulation than from the capsule formulation. There were no relevant differences in the safety and tolerability profiles between the different formulations. The two polymorphic forms of ponesimod and tablet versus capsule formulations were similar in terms of pharmacokinetics, safety, and tolerability.


Glycosylation of human cyclooxygenase-2 (COX-2) decreases the efficacy of certain COX-2 inhibitors.
Prostanoids play an important role in a variety of physiological and pathophysiological processes including inflammation and cancer. The rate-limiting step in the prostanoid biosynthesis pathway is catalyzed by cyclooxygenase-2 (COX-2). COX-2 exists as two glycoforms, 72 and 74 kDa, the latter resulting from an additional glycosylation at Asn(580). In this study, Asn(580) was mutated, and the mutant and wild-type COX-2 genes were expressed in COS-1 cells to determine how glycosylation affects the inhibition of COX-2 activity by aspirin, flurbiprofen, ibuprofen, celecoxib, and etoricoxib. Results indicate that certain inhibitors were 2-5 times more effective at inhibiting COX-2 activity when the glycosylation site was eliminated, indicating that glycosylation of COX-2 at Asn(580) decreases the efficacy of some inhibitors.


Stress induced experimental colitis.
Stress induces chemical changes in the central nervous system which alters the biochemistry and physiology of the digestive tract. The present study determines arachidonic acid oxidation and damage in the colon following stress. Ten rats were stressed by the cold-restraint method; ten were controls. Stress induced 0.5 +/- 0.7 (S.D.) mucosal erosions whereas controls had none. Subepithelial hemorrhage and erosions occurred only in the proximal two-thirds of the colon. Prostaglandin E(2) synthesis was increased after stress compared to the control (381 +/- 130 vs. 1610 +/- 372 ng/g/min). Leukotriene C(4) synthesis also increased after stress (4217 +/- 994 vs. 11300 +/- 1662 ng/g/min). Synthesis of prostaglandin E(2) increased (r = 0.9381) with leukotriene C(4). The response of the colon to stress is less severe than that in the stomach and may be related to regional regulation of prostaglandin and leukotriene synthesis.


SIRT1 expression is associated with lymphangiogenesis, lymphovascular invasion and prognosis in pN0 esophageal squamous cell carcinoma.
Sirtuin1 (SIRT1) is an NAD(+)-dependent type III histone deacetylase (HDAC). This research investigated the prevalence of SIRT1 protein expression and its prognostic influence with the aim of validating its potential role in lymphangiogenesis and lymphovascular invasion (LVI) in pN0 esophageal squamous cell carcinoma (ESCC). A total of 206 patients were enrolled in this retrospective study. SIRT1 and VEGF-C protein expression was detected by immunohistochemical staining. Peritumoral lymphatic microvessel density (LVD) and LVI were evaluated by immunostaining for D2-40. Statistical analysis was then preformed to investigate the relevance of SIRT1 expression and various clinicopathologic features and to examine the effect of SIRT1 on tumor-induced lymphangiogenesis, LVI and prognosis. SIRT1 positive expression was identified in 95 cases in the nucleus and was significantly correlated with T status (P < 0.001), disease stage (P = 0.001), VEGF-C positive expression (P = 0.015), high LVD (P = 0.013) and positive LVI (P = 0.015). Patients with SIRT1 positive expression, high LVD and positive LVI had a significantly unfavorable 5-year disease free survival (P < 0.001, P = 0.030, and P < 0.001, respectively) and overall survival (P < 0.001, P = 0.017, and P < 0.001, respectively). However, based on multivariate Cox regression analysis, only SIRT1 positive expression and positive LVI were significant independent prognosticators of poor disease-free survival (P = 0.029 and 0.018, respectively) and overall survival (P = 0.045 and 0.031, respectively). SIRT1 positive expression was significantly associated with tumor progression, lymphangiogenesis, LVI and poor survival in pN0 ESCC patients. Our research shows a utilization of SIRT1 in prognosing poor survival and providing possible target for ESCC patients through inhibiting its lymphangiogenesis activity.


[Use of simvatin for obliterating atherosclerosis after reconstructive operations on the main arteries of the lower extremities].
The results of application of simvatin in 207 patients after performance of reconstructive operations on the main arteries of femoro-popliteo-tibial segment were analyzed. Durable usage of simvatin had permitted to improve the immediate and the late results of reconstructive operations, to lower postoperative lethality significantly, caused by cardiovascular and vascular-cerebral insufficiency.


Changes in electronic couplings of mixed-valence systems due to through-space intramolecular interactions.
The strength of the electronic interactions between the two redox moieties in fullerene-substituted mixed-valence bis(ferrocenylethynyl)ethene derivatives is modulated by the through-space intramolecular electronic interactions of C(60) with the bridging conjugated system.


[Effect of clinical and laboratory management in preparation of combined crowns faced with porcelain on the state of periodontal soft tissues].
The effect of clinical management and laboratory procedures during preparation of porcelain-faced combined crowns is discussed. Attention is called to proper grinding of dental surfaces, with particular reference to the area near the gingiva. The result of the treatment with porcelain-faced crowns depended not only on the clinical management but also on a proper shape of the metal part of the crown and proper laying and baking of porcelain. This procedure should be done strictly according to the instruction of the producer.


Does in-patient ECG monitoring have an impact on medical care in chronic heart failure patients?
Heart failure patients' management in non-intensive care units might be improved by telemetry monitoring. However, telemetry adds the cost and evidence of this effectiveness is not available. To evaluate the utility of the ECG monitoring in chronic heart failure patients admitted to a non-intensive care unit. A prospective analysis of the utility of telemetry in 711 patients admitted to a Heart Failure Unit from March 1996 to September 1997. One hundred and ninety-nine patients underwent telemetry; 108 telemetry findings were recorded, in 35% of NYHA class II, in 46% in NYHA class III-IV and 43% in unstable patients. Reasons for telemetry were: known arrhythmia (n=82), electrolytes disturbances (n=20), atrial fibrillation (n=12), symptoms (n=48), i.v. dobutamine (n=13), drugs control (n=16), devices control (n=8). Crossing reasons for telemetry and detected events we had, respectively, 63, 11, 2, 17, 5, 6, and 0 telemetry findings. Treatment was guided by telemetry results in only 33 cases (respectively in 18, 0, 4, 5, 5, 1, and 0 cases). Physicians perceived telemetry as unhelpful in 30% of cases; as helpful in 70%. The percentage of inutility, usefulness with and without related medical intervention were similar between stable and unstable patients (30, 18, 51% and 31, 15, 54%, respectively). In a heart failure unit ECG monitoring is mostly used in severe and unstable patients. However, medical decisions are rarely guided by the telemetry findings. The usefulness of telemetry might be underestimated because one of the uncounted results might be the avoidance of inappropriate intervention.


[Comparison of selected physiological indicators and vegetative system tests in a group of turbine assemblers in relation to age and duration of employment].
The examinations covered 37 men--turbine assemblers--at the Thermal--electric Power Station Plant in Lódź. The subjects were classified by age into three groups: 21--30 years, 21--40 years and over 40 years and--by employment, length: 1--10 years, 11--20 years and over 20 years. All subjects underwent tests of selected physiological indices and vegetative system tests. The obtained results were compared in groups by age and employment duration. Most differences between particular groups were found to be insignificant. Significant differences referred to the same indices and vegetative system tests in both groups compared and were similar. The examinations indicated that it's of no matter whether in the tests are compared depending on age or employment duration.


Evaluation of Cardiotonic Steroid Modulation of Cellular Cholesterol and Phospholipid.
We have previously shown that 21-benzylidene digoxin (21-BD) increases the total cholesterol and phospholipid content on the membrane of HeLa cells. Lipid modulation caused by cardiotonic steroids (CTS) is still unexplored. Therefore, the aim of the present study was to evaluate the cholesterol and phospholipid modulation of the cell membrane caused by ouabain and 21-BD and the possible involvement of the caveolae on this modulation. For this, one cell line containing caveolae (HeLa) and other not containing (Caco-2) were used. The modulation of the lipid profile was evaluated by total cholesterol and phospholipids measurements, and identification of membrane phospholipids by HPTLC. The cholesterol distribution was evaluated by filipin staining. The caveolin-1 expression was evaluated by Western Blotting. Ouabain had no effect on the total membrane lipid content in both cell lines. However, 21-BD increased total membrane phospholipid content and had no effect on the membrane cholesterol content in Caco-2 cells. CTS were not able to alter the specific phospholipids content. In the filipin experiments, 21-BD provoked a remarkable redistribution of cholesterol to the perinuclear region of HeLa cells. In Caco-2 cells, it was observed only a slight increase in cholesterol, especially as intracellular vesicles. The caveolin-1 expression was not altered by any of the compounds. Our data mainly show different effects of two cardiotonic steroids. Ouabain had no effect on the lipid profile of cells, whereas 21-BD causes important changes in cholesterol and phospholipid content. Therefore, the modulation of cholesterol content in the plasma membrane of HeLa cells is not correlated with the expression of caveolin-1.


Distribution of primary vestibular fibers in the brainstem and cerebellum of the monkey.
Attempts were made to determine the central projections of ganglion cells innervating individual semicircular ducts in the monkey by implanting or injecting tritiated amino acids (leucine and/or proline), or horseradish peroxidase (HRP), selectively into a single ampulla. Central transport via the vestibular ganglion in animals receiving isotope implants or injections fell into three categories: (1) transport from ganglion cells innervating all receptive elements of the labyrinth, (2) transport from ganglion cells innervating the three semicircular ducts, and (3) transport from cells of the inferior vestibular ganglion innervating the posterior semicircular duct. Transneuronal transport of isotope was observed in secondary vestibular fibers in animals where proline was used and survival exceeded 12 days. Transneuronal labeling of secondary auditory fibers was independent on the [3H]amino acid used, and occurred with survivals of 10 or more days. HRP implanted into the ampulla of the lateral semicircular duct in several animals produced retrograde transport to efferent vestibular and cochlear neurons, but did not result in transganglionic labeling of primary vestibular or auditory fibers. Primary vestibular fibers terminate throughout the superior (SVN) and medial vestibular nuclei (MVN). Within SVN, terminals are most pronounced in its central large-celled portion, but extend into peripheral parts of the nucleus, except for a small medial area near its junction with the oral pole of MVN. Primary projections to MVN are homogenously distributed throughout the nucleus excepting a small circular area of sparse terminals along its ventral margin. Primary vestibular afferents terminate mainly in rostral and caudal portions of the inferior vestibular nucleus (IVN), but do not reach cell group 'f'. Projections to the lateral vestibular nucleus (LVN) are restricted to its ventral part. Primary projections to the accessory vestibular nuclei reach the interstitial nucleus of the vestibular nerve (NIVN) and cell group 'y'. Fibers project beyond the vestibular nuclei (VN) to terminate ipsilaterally in the accessory cuneate nucleus (ACN), the subtrigeminal lateral reticular nucleus (SLRN), and well-defined portions of the reticular formation (RF). Projections to SVN and MVN are derived primarily from ganglion cells innervating the semicircular ducts, while projections to caudal IVN, cell group 'y' and ACN are related mainly to macular portions of the vestibular ganglion. NIVN receives both macular and duct afferents.(ABSTRACT TRUNCATED AT 400 WORDS)


Conversion of glycine max seed agglutinins from nonspecific to anti-(A + B).
The seeds of glycine max contain agglutinins which are typically nonspecific in their reactivity. Our investigations show that the phytagglutinins in GM can be converted from nonspecific to anti-(A + B) after the lectin is absorbed with horse red cells. The anti-A and anti-B fractions can be further separated by suitably absorbing the lectin with human red cells. The lectin absorbed with horse red cells or with group-0 human red cells shows an A-stressed activity.


Multiplexed High Resolution Melting Assay for Versatile Sample Tracking in a Diagnostic and Research Setting.
Modern experimental procedures in molecular genetics, such as next-generation sequencing experiments, require that samples are taken along a whole series of wet- and dry-laboratory steps. It generally is accepted that by increasing the complexity and number of steps in the experimental pipeline, the risk of sample swaps increases. It therefore is recommended to confirm the identity of each individual sample at the end of any pipeline. Here, we present a versatile assay to determine the identity of samples rapidly and efficiently by genotyping 21 single-nucleotide polymorphisms (SNPs) using multiplex high resolution melting. The selected SNPs also are present in whole-exome sequencing data, and comparison of the differentially obtained genotypes allows reliable identification of individual samples. In this assay, we combined primers interrogating two to three SNPs per high resolution melting reaction, enabling the generation of the SNP genotype profile in only eight reactions per sample, limiting the hands-on time and minimizing the amount of reagents. This SNP profiling approach also can be used to track samples in custom next-generation sequencing enrichment panels by including these 21 SNPs in the target region, allowing for the often-required independent validation of sample identity in both clinical and research settings.


Mechanisms of late recurrence after radical surgery for gastric carcinoma.
Factors involved in late recurrence of gastric carcinoma were investigated in 25 patients with late recurrence who died five or more years after radical surgery and 129 with early recurrence who died within two years after surgery. In the patients with late recurrence, the important routes of cancer spread in the initial phase of the recurrence were contiguous invasion and lymphatic spread. Whether early or late recurrence occurred had a high correlation with the following four conditions: (1) the amount of residual cancer left at the time of surgery; (2) the spread of the residual cancer; (3) the rate of cancer proliferation; and (4) the resistance of the host. To prevent late recurrence, it is necessary not to leave any cancer tissue in these routes at the time of gastrectomy, as well as to employ adjuvant chemo- and immunotherapy for the inhibition of cancer proliferation and elevation of the host resistance.


Deficit in cognitive shifting ability in patients with obsessive-compulsive disorder.
Reports on cognitive test deficits in patients with obsessive-compulsive disorders and interpretations of the underlying dysfunction have been conflicting. In the present study, 15 obsessive-compulsive patients were compared with 15 matched normal controls on three types of test sensitive to: spatial ability, ability to shift cognitive set, and combinations of both. Performance deficits as compared with controls were shown in Block Design, the Short Wisconsin Card Sort, the Word Fluency Test, and on the Money Road Map Test. No deficits were present on a number of other measures. The pattern of results is interpreted partly as revealing deficits in ability to shift cognitive set, more particularly with nonverbal material.


Graft function, histopathology and morphometry of radial arteries used as conduits for myocardial revascularization in patients beyond age 70.
Coronary artery bypass grafting (CABG) using radial arteries has become a standard procedure for younger patients in many centers. However, advanced atherosclerotic changes may limit its use in older patients. We studied the effects of age on morphologic and histopathologic findings in CABG patients aged 70 years and older. In 31 consecutive patients aged 70-85 (mean 77+/-8 years) scheduled for elective CABG, the left or right radial artery (RA) was used to graft the second target vessel (first graft: LIMA-LAD). Preoperative Doppler flow and Allen's test were satisfactory. Intraoperatively the distal segment adjacent to the anastomosis site of the RA was collected for histologic evaluation. Intraoperative angiography, measurement of flow, and resistance index (PI) were performed to document graft quality. Histopathology and morphometry were used to measure intimal and medial areas (IA, MA; microm2), intimal thickening index (ITI), relation between intimal and medial width at maximum intimal thickness (IMR), and percentage of luminal narrowing (%LN). The RA showed no evidence for stenosis of the conduits or the anastomosis. In all grafts flow and PI were satisfactory (76+/-14 ml/min; PI: 2.2+/-0.9). Histopathology and morphometry showed atherosclerotic changes in all RA grafts: IA: 890+/-971 (range 286-5244), MA: 2751+/-818 (range 1357-4989), ITI: 0.26+/-0.09 (range 0.12-0.44), IMR: 0.59+/-0.28 (range 0.21-1.13) %LN: 38+/-5 (range 13.2-61.7). Age as well as classic risk factors including diabetes, hypertension, smoking, and hyperlipidemia did not correlate with RA atherosclerosis. Excellent macroscopic and angiographic results were obtained. All grafts used showed minor to moderate atherosclerotic changes without severely altered indices of intimal thickening or luminal narrowing. The radial artery must be used with caution; however, age should not be an exclusion criterion per se.


Membrane protein from rabbit T-lymphocytes, specifically binding staphylococcal enterotoxin A (SEA).
The presence of specific binding of SEA with membranes of lymphocytes from rabbit thymus is established. Components of a glycolipid nature are absent in the composition of the receptor complex for SEA on T-lymphocytes. Suitable conditions for the solubilization of the receptor membrane fraction by Triton X-100 are described. The SEA-binding membrane fraction is isolated by means of an affinity-chromatography method. The main component of the fraction is a protein with molecular mass 42 kd. The isolated protein inhibits the specific binding of [125I] SEA on cell (T-lymphocytes) and subcell (membrane) levels.


Hearing loss and deafness in the pediatric population: causes, diagnosis, and rehabilitation.
With prevalence figures close to 0.2% at birth and rising to 0.35% during adolescence, hearing loss is the most frequent sensory impairment in childhood. This silent handicap has to be actively sought for without delay as it will seriously interfere with the development of speech, language, cognitive and socio-emotional behavior. Objective physiological techniques (evoked potentials, oto-acoustic emissions, tympanometry) combined according to the cross-check principle allow early diagnosis. Objective testing yields invaluable information about the mechanism of the loss and the contribution of disruption of the neural code to the handicap. Among the acquired causes, cytomegalovirus (CMV) infections plays a major role and may take elusive forms. Aminoglycoside ototoxicity has a genetic determinant. Meningitis can lead to rapid endocochlear ossification prompting for rapid cochlear implantation. Genetic causes account for more than 60% of congenital hearing loss, new genetic causes being discovered at an amazing rate. The high number of genetic entities and their huge heterogeneity among them requires guidelines for requesting genetic testing when desirable. Several syndromes prone to request neuropediatricians' attention as an early diagnosis followed by specific treatment can considerably limit the ensuing handicap. Whatever the type of assistive device fitted (amplifying hearing aid or cochlear implant) and the importance of associated handicaps, a multidisciplinary rehabilitation combined with educated parental commitment is necessary for optimal results.


Mutagenesis and molecular dynamics suggest structural and functional roles for residues in the N-terminal portion of the cytochrome P450 2B1 I helix.
To investigate their potential roles in ligand access, binding, and subsequent metabolism, residues in the N-terminal portion of the cytochrome P450 2B1 I helix were mutated to alanine and phenylalanine. Of the 18 mutants from E286 to S294 only 7 yielded holoprotein in an Escherichia coli expression system. Substitutions at positions 289, 290, 292, and 294 caused >/= 2-fold changes in kcat and/or Km for two or more of the 2B1 substrates examined, testosterone, 7-ethoxy-4-trifluoromethylcoumarin, 7-benzyloxyresorufin, and benzphetamine. I290 substitutions had the largest effects on steady-state parameters for three substrates and increased benzphetamine affinity. Steered molecular dynamics simulations of testosterone egress along the I helix identified hydrophobic interactions with I290, L293, and S294 and water bridges to E286 and S294. Sensitivity of holoprotein formation to substitution and effects on substrate binding and metabolism suggest structural and functional roles for residues in the N-terminus of the cytochrome P450 2B1 I helix.


Rhabdomyolysis and renal failure--unusual complications of drug abuse. A case report.
We report a case of acute rhabdomyolysis following the abuse of opiates injected intravenously. The patient also developed mild renal failure as well as transient myocarditis. The pathogenesis and management of the condition are discussed.


[Regulatory requirements regarding cell-based medicinal products for human and veterinary use - a comparison].
At present, there is no separate regulatory framework for cell-based medicinal products (CBMP) for veterinary use at the European or German level. Current European and national regulations exclusively apply to the corresponding medicinal products for human use. An increasing number of requests for the regulatory classification of CBMP for veterinary use, such as allogeneic stem cell preparations and dendritic cell-based autologous tumour vaccines, and a rise in scientific advice for companies developing these products, illustrate the need for adequate legislation. Currently, advice is given and decisions are made on a case-by-case basis regarding the regulatory classification and authorisation requirements.Since some of the CBMP - in particular in the area of stem-cell products - are developed in parallel for human and veterinary use, there is an urgent need to create specific legal definitions, regulations, and guidelines for these complex innovative products in the veterinary sector as well. Otherwise, there is a risk that that the current legal grey area regarding veterinary medicinal products will impede therapeutic innovations in the long run. A harmonised EU-wide approach is desirable. Currently the European legislation on veterinary medicinal products is under revision. In this context, veterinary therapeutics based on allogeneic cells and tissues will be defined and regulated. Certainly, the legal framework does not have to be as comprehensive as for human CBMP; a leaner solution is conceivable, similar to the special provisions for advanced-therapy medicinal products laid down in the German Medicines Act.


Youth depression and inflammation: Cross-sectional network analyses of C-Reactive protein, interleukin-6 and symptoms in a population-based sample.
Inflammation-related proteins constitute a promising avenue in studying biological correlates of major depressive disorder (MDD). However, MDD is a heterogeneous condition - a crucial aspect to be considered in association studies. We examined whether inflammatory proteins are associated with categorical diagnosis, a dimensional total sum-score, and specific depressive symptoms among youths. We analyzed data from the 1993 Pelotas Birth Cohort, a population-based study in Brazil that followed individuals up to age 22 years. Categorical psychiatric diagnoses were derived using adapted modules of the Mini International Neuropsychiatric Interview (MINI). Dimensional symptomatology was assessed using the Brazilian Portuguese version of the Center for Epidemiological Studies-Depression Scale-Revised (CESD-R). We estimated network structures that included individual depressive symptoms as measured by CESD-R items, peripheral inflammatory markers (C-Reactive Protein [CRP] and Interleukin-6 [IL-6]), as well as relevant covariates. We evaluated 2586 participants (mean age = 22.5[SD = 0.33]) There were no associations between concentrations of inflammatory proteins and categorical diagnosis of MDD or with CESD-R total sum-scores. In symptom-specific analysis, CRP and IL-6 were positively connected to somatic and cognitive items. We found cross-sectional connections of two commonly studied inflammatory proteins and specific depressive symptoms. Conducting symptom-specific analyses in relation to biological markers might advance our understanding of the heterogeneity of MDD.


A method for specific cloning and sequencing of human hprt cDNA for mutation analysis.
A method has been developed for the specific amplification and cloning of human hprt cDNA which can be used for mutant sequence analysis. Messenger RNA is isolated from TK6 lymphoblasts and is used to produce a first strand cDNA with reverse transcriptase primed with oligo dT. Second strand synthesis and subsequent amplification of hprt sequences is accomplished using Thermus aquaticus DNA polymerase and hprt-specific primers in the polymerase chain reaction (PCR) procedure. Convenient restriction enzyme sites have been built into the 5' ends of the PCR primers to allow cloning of the hprt fragments in M13mp19. Dideoxy sequencing of hprt with specific primers can be carried out using either the PCR reaction product or fragments cloned in M13mp19 as substrate. This general cloning/sequencing method can be used to analyze hprt mutation in human cells obtained both in vitro and in vivo.


Theta-paced flickering between place-cell maps in the hippocampus.
The ability to recall discrete memories is thought to depend on the formation of attractor states in recurrent neural networks. In such networks, representations can be reactivated reliably from subsets of the cues that were present when the memory was encoded, at the same time as interference from competing representations is minimized. Theoretical studies have pointed to the recurrent CA3 system of the hippocampus as a possible attractor network. Consistent with predictions from these studies, experiments have shown that place representations in CA3 and downstream CA1 tolerate small changes in the configuration of the environment but switch to uncorrelated representations when dissimilarities become larger. However, the kinetics supporting such network transitions, at the subsecond timescale, is poorly understood. Here we show in rats that instantaneous transformation of the spatial context does not change the hippocampal representation all at once but is followed by temporary bistability in the discharge activity of CA3 ensembles. Rather than sliding through a continuum of intermediate activity states, the CA3 network undergoes a short period of competitive flickering between preformed representations of the past and present environment before settling on the latter. Network flickers are extremely fast, often with complete replacement of the active ensemble from one theta cycle to the next. Within individual cycles, segregation is stronger towards the end, when firing starts to decline, pointing to the theta cycle as a temporal unit for expression of attractor states in the hippocampus. Repetition of pattern-completion processes across successive theta cycles may facilitate error correction and enhance discriminative power in the presence of weak and ambiguous input cues.


Xylazine effects on opioid-induced brain hypoxia.
Xylazine has emerged in recent years as an adulterant in an increasing number of opioid-positive overdose deaths in the United States. Although its exact role in opioid-induced overdose deaths is largely unknown, xylazine is known to depress vital functions and cause hypotension, bradycardia, hypothermia, and respiratory depression. In this study, we examined the brain-specific hypothermic and hypoxic effects of xylazine and its mixtures with fentanyl and heroin in freely moving rats. In the temperature experiment, we found that intravenous xylazine at low, human-relevant doses (0.33, 1.0, 3.0 mg/kg) dose-dependently decreases locomotor activity and induces modest but prolonged brain and body hypothermia. In the electrochemical experiment, we found that xylazine at the same doses dose-dependently decreases nucleus accumbens oxygenation. In contrast to relatively weak and prolonged decreases induced by xylazine, intravenous fentanyl (20 μg/kg) and heroin (600 μg/kg) induce stronger biphasic brain oxygen responses, with the initial rapid and strong decrease, resulting from respiratory depression, followed by a slower, more prolonged increase reflecting a post-hypoxic compensatory phase, with fentanyl acting much quicker than heroin. The xylazine-fentanyl mixture eliminated the hyperoxic phase of oxygen response and prolonged brain hypoxia, suggesting xylazine-induced attenuation of the brain's compensatory mechanisms to counteract brain hypoxia. The xylazine-heroin mixture strongly potentiated the initial oxygen decrease, and the pattern lacked the hyperoxic portion of the biphasic oxygen response, suggesting more robust and prolonged brain hypoxia. These findings suggest that xylazine exacerbates the life-threatening effects of opioids, proposing worsened brain hypoxia as the mechanism contributing to xylazine-positive opioid-overdose deaths.


Decline in sialic acid composition of cellular membranes isolated from ovine corpora lutea during prostaglandin-induced luteolysis: apparent independence of autoimmune recognition.
Sialic acid was quantified in plasma membranes of corpora lutea isolated during prostaglandin (PG) F2 alpha-induced luteolysis in sheep. Concentrations of sialic acid within membranes decreased after injection of PGF2 alpha, and before signs of luteal regression (i.e., a decline in tissue concentrations of progesterone) were manifested. Removal of residues of sialic acid from luteal membranes was not associated with cellular binding of gamma globulin, as monitored by indirect immunofluorescence microscopy. We suggest that desialylation of luteal membranes could be an important aspect of the mechanism of luteolysis. Such a process does not appear to involve participation of autoantibody.


Reaction mechanisms of peroxyl and C-centered radicals with sulfhydryls.
Rate constants for reactions of a peroxyl (CCl3OO.) and C-centered radicals, that is, phenyl (.C6H4CH2COO-) and vinyl (uracil-5-yl), with an aromatic thiol (p-CH3OC6H4SH) were measured over a pH range (3-12) to include ArSH and ArS- forms. The pH dependence of these rate constants indicates that peroxyl radicals react by a redox mechanism while the C-centered radicals react by an H-atom transfer process. The different mechanisms encountered in the repair of various radicals suggest design features to be incorporated into antiagents, such as radioprotectors and anticarcinogens.


Optimization of Strategy for Modified mRNA Inducing Cardiac-Specific Expression in Mice.
Lipid nanoparticle (LNP)-coated-modified RNA(modRNA) has been developed for enhancing the stability of modRNA, but it tends to accumulate in liver. The current study aimed to optimize strategy for increasing cardiac expression efficiency of modRNA. We synthesized Luciferase (Luc)-modRNA, and also developed 122Luc modRNA, a liver silencing Luc modRNA. Intramyocardial injection of naked Luc modRNA induced high bioluminescence signal in heart, but very low in other organs including liver. Luc modRNA-LNP injection showed the signal was increased by 5 folds in the heart and by 15,000 folds in the liver, compared to naked Luc modRNA group. In comparison with Luc modRNA-LNP group, the liver signal was decreased to 0.17%, while cardiac signal showed a slight drop by intramyocardial injection of 122Luc-modRNA-LNP. Our data revealed that intramyocardial injection of naked modRNA could effectively induced cardiac-specific expression. For cardiac delivery of Luc modRNA-LNP, 122modRNA-LNP enhances specificity of cardiac expression by abolishing liver signal.


Static Injection, Migration, and Equalization (SIME): A New Paradigm for Safe Ultrasound-Guided Brazilian Butt Lift: Safer, Faster, Better.
Although the Brazilian butt lift (BBL) is one of the most popular procedures in body contouring, it has been associated with the risk of pulmonary fat embolism when fat graft is injected into the gluteal muscles. The subcutaneous plane has been identified as a safe site for fat graft injection, but deaths from fat embolism continue to occur because there is no mechanism to confirm consistent subcutaneous placement. The aim of this paper was to determine if real-time intraoperative ultrasound could accurately identify the subcutaneous gluteal anatomic landmarks and permit a single surgeon to consistently target fat graft placement in the subcutaneous space. In total, 4150 BBLs were performed with real-time intraoperative ultrasound being used to confirm the subcutaneous position of a static cannula during fat graft injection. Serial deposits of fat graft were performed in each buttock. Ultrasound confirmed that fat graft consistently remained above the deep gluteal fascia and migrated through the deep subcutaneous space. These fat graft deposits were then equalized with a moving cannula to correct any contour deformities. Operative times were recorded and compared with BBL performed by expansion vibration lipofilling without ultrasound. Real-time intraoperative ultrasound allowed for the visual confirmation of consistent subcutaneous fat graft deposition and the targeting of fat graft into specific gluteal subcutaneous compartments. Real-time intraoperative ultrasound allows the surgeon to confirm a subcutaneous-only fat graft injection, target specific gluteal subcutaneous compartments, and take advantage of the unique architecture of the deep subcutaneous space to create gluteal projection and correct contour deformities.


Late remote ischemic preconditioning in children undergoing cardiopulmonary bypass: a randomized controlled trial.
Cardiopulmonary bypass is associated with ischemia-reperfusion injury to multiple organs. We aimed to evaluate whether remote ischemic preconditioning performed the day before surgery for congenital heart disease with cardiopulmonary bypass attenuates the postoperative inflammatory response and myocardial dysfunction. This was a prospective, randomized, single-blind, controlled trial. Children allocated to remote ischemic preconditioning underwent 4 periods of 5 minutes of lower limb ischemia by a blood pressure cuff intercalated with 5 minutes of reperfusion. Blood samples were collected 4, 12, 24, and 48 hours after cardiopulmonary bypass to evaluate nuclear factor kappa B activation in leukocytes by quantification of mRNA of I kappa B alpha by real-time quantitative polymerase chain reaction and for interleukin-8 and 10 plasma concentration measurements by enzyme-linked immunosorbent assay. Myocardial dysfunction was assessed by N-terminal pro-B-type natriuretic peptide and cardiac troponin I plasma concentrations, measured by chemiluminescence, and clinical parameters of low cardiac output syndrome. Twelve children were allocated to remote ischemic preconditioning, and 10 children were allocated to the control group. Demographic data and Risk Adjustment for Congenital Heart Surgery 1 classification were comparable in both groups. Remote ischemic preconditioning group had lower postoperative values of N-terminal pro-B-type natriuretic peptide, but cardiac troponin I levels were not significantly different between groups. Interleukin-8 and 10 concentrations and I kappa B alpha gene expression were similar in both groups. Postoperative morbidity was similar in both groups; there were no postoperative deaths in either group. Late remote ischemic preconditioning did not provide clinically relevant cardioprotection to children undergoing cardiopulmonary bypass.


Long-term effectiveness of advanced hybrid closed loop in children and adolescents with type 1 diabetes.
Advanced hybrid closed loop (AHCL) systems are the newest tool to improve metabolic control in type 1 diabetes (T1D). Long-term glycemic control of children and adolescents with T1D switching to MiniMed™ 780G in a real clinical setting was evaluated. Time in range (TIR) and in different glucose ranges, glycemic variability indexes, HbA1c and basal-bolus insulin distribution were evaluated in 44 subjects (mean age 14.2 ± 4.0 years, 22 males) during manual mode period, first 14 days (A14d) and first month after auto-mode activation (A1M), first 14 days after 3 months (A3M) and 6 months (A6M) in auto-mode. Mean TIR at A14d was 76.3 ± 9.6% versus 69.3 ± 12.6% in manual mode (p < 0.001), and this improvement was maintained over 6 months. Subjects with TIR >70% and >80% in manual mode were 45% and 23%, respectively, and increased to 80% (p = 0.041) and 41% (p = 0.007) at A14d. Basal-bolus distribution changed in favor of bolus, and auto-correction boluses inversely correlated with TIR. HbA1c was 7.2 ± 0.7% (55 mmol/mol) at baseline and significantly improved after 3 months (6.7 ± 0.5%, 50 mmol/mol, p < 0.001) and 6 months (6.6 ± 0.5%, 49 mmol/mol, p < 0.001). TIR was higher in individuals >13 years at all time periods (p < 0.001). Glycemic target <120 mg/dl was associated with better TIR. AHCL MiniMed™ 780G allowed rapid and sustained improvement of glycemic control in young T1D patients, reaching recommended TIR. Teenagers showed good technology adherence with optimal TIR, maintained better over time compared to younger children. Stricter settings were associated with better metabolic control, without increase in severe hypoglycemia occurrence.


B7-H3 specific CAR-T cells exhibit potent activity against prostate cancer.
B7-H3 is an attractive target for immunotherapy because of its high expression across multiple solid tumors, including prostate cancer, and restricted expression in normal tissues. Among various types of tumor immunotherapy, chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in hematological tumors. However, the potency of CAR-T cell therapy in solid tumors is still limited. Here, we examined the expression of B7-H3 in prostate cancer tissues and cells and developed a second-generation CAR that specifically targets B7-H3 and CD28 as costimulatory receptor to explore its tumoricidal potential against prostate cancer in vitro and in vivo. The high expression of B7-H3 was detected on both the surface of PC3, DU145 and LNCaP cells and prostate cancer tissues. B7-H3 CAR-T cells efficiently controlled the growth of prostate cancer in an antigen-dependent manner in vitro and in vivo. Moreover, tumor cells could induce the proliferation of CAR-T cells and the release of high levels of cytokines of IFN-γ and TNF-α in vitro. Results demonstrated that B7-H3 is a potential target for prostate cancer therapy that supports the clinical development of B7-H3 specific CAR-T cells for prostate cancer.


Child abuse in blended households: reports from runaway and homeless youth.
Building upon prior research that reveals an elevated risk of abuse to children in blended households, the study considers whether risk of abuse varies by the type of non-related parent figure (i.e., stepparent, adoptive parent, or cohabiting adult) in residence. A sample of 40,000 youths that sought services from runaway and homeless youth shelters in the US was examined. Holding constant the presence of a natural parent, the study evaluated the risk of abuse by the presence and type of an additional parent figure in the home. Compared with other household types, an elevated risk of sexual and physical abuse was observed for youths from homes with a non-related parent figure in residence. Among youths from blended homes, the risk of abuse was not found to vary as a function of the type of non-related parent figure in the home. The study results are consistent with prior research that shows the presence of a non-related parent figure in a household is associated with a greater than expected risk of sexual or physical abuse to children. However, the findings suggest that the particular role or status of non-related parents may not be a meaningful risk factor when considering intervention strategies in suspected cases of abuse in blended households. The sample probably represents family conditions that are significantly worse for children than what would be found in the general population, and thus the results of this study should not be generalized to the population at large.


Fungal diversity at fragmented landscapes: synthesis and future perspectives.
Fungi are organisms with important roles in ecosystem functioning and services, but knowledge about how habitat fragmentation affect fungal diversity is biased by experimental approaches and it is spread in different trophic groups. We analyzed the empirical evidences of fungal diversity in fragmented landscapes, and proposed future perspectives for the study of these organisms under land use changes. Fungal diversity might be negatively affected by habitat fragmentation; however, this trend may differ in magnitude depending on fungal groups and their nutritional habits. In addition, due to the fact that fungal diversity at fragmented landscapes has been studied mainly through few indicators (e.g. isolation, area and edge effect); we propose incorporating the landscape structure and accurate spatio-temporal scales to the study of fungal diversity responses to fragmented landscapes. Together, this methodological refinement may allow improving knowledge on fungi when designing proper strategies for landscape management.


Survival advantage with para aortic lymphadenectomy in peri-ampullary cancer: A retrospective cohort study.
Metastatic para aortic lymph nodes (PALN) in patients with peri ampullary cancer entail poor prognosis. Role of curative surgery in these patients remains debatable. The objective of the current study was to evaluate outcome after extended pancreaticoduodenectomy (PD) in patients with and without positive PALN. We reviewed 65 patients who underwent extended PD with PALN removal between 2011 and 2014. Patients were divided into two groups; those with positive PALN and those without. Patients were sub classified for pancreatic and non-pancreatic cancer. Outcome was determined based on median and estimated 3 year overall survival. Median age was 57 (32-85) years. PALN were involved in 15 (23%) patients. Overall 3 year survival for patients with and without positive PALN was 60% and 54% (P = 0.7). Significant difference in survival was present between patients with pancreatic cancer and positive PALN [9 (3-12) months] versus non-pancreatic cancers with positive PALN [17.5 (13-38) months] (P = 0.02). Four out of five patients with pancreatic cancer and positive PALN had survival >6 months and 3 out of these 5 patients were alive at the last follow up. Curative surgery may benefit some patients with pancreatic cancer and positive PALN and should be considered selectively.


Normalisation of insulin-like growth factor-I does not improve insulin action in cirrhosis.
Cirrhosis of the liver is characterised by insulin resistance and low levels of insulin-like growth factor I (IGF-I). Lack of IGF-I may contribute to this insulin resistance, as IGF-I increases insulin sensitivity. This study aimed to determine the effects of normalisation of IGF-I on insulin action in cirrhosis. This article is a randomised sequence-crossover placebo controlled study. Eight patients with cirrhosis and eight controls were studied following treatment with IGF-I (50 μg/kg twice daily) or saline. Insulin action, glucose utilisation and endogenous glucose production were measured during the euglycaemic hyperinsulinaemic clamp. The patients with cirrhosis had normal fasting glucose level, but increased levels of insulin (P < 0.05) and C-peptide (P < 0.05). Insulin resistance resulted from a defect in glycogen synthesis, whereas insulin-mediated suppression of glucose production was unaltered. In cirrhosis, IGF-I treatment normalised free (from 0.07 ± 0.01 to 0.26 ± 0.05 μg/L) and total IGF-I (from 73 ± 6 to 250 ± 39 μg/L), whereas in controls, the IGF-I level increased into the upper physiological range (free IGF-I from 0.23 ± 0.02 to 0.61 ± 0.06 μg/L; total IGF-I from 200 ± 19 to 500 ± 50 μg/L) (all P-values < 0.05). In cirrhosis, IGF-I treatment did not change fasting glucose, insulin or C-peptide levels (P > 0.05). In the controls, insulin and C-peptide levels decreased (P < 0.05). IGF-I treatment did not improve insulin sensitivity in cirrhosis. Because normalisation of IGF-I levels did not affect insulin sensitivity lack of IGF-I is unlikely to result in insulin resistance in cirrhosis. IGF-I supplementation is therefore unlikely to improve insulin action in patients with cirrhosis.


Antagonism by droperidol of dopamine-induced relaxation in isolated dog arteries.
Dopamine caused a dose-related relaxation in helically cut strips of dog coronary and renal arteries treated with phenoxybenzamine andcontracted with prostaglandin F2 alpha. The dose-response curve to dopamine was shifted to the right by droperidol in concentrations above 3 X 10(-5) M. Adenosine-induced relaxations were not attenuated by droperidol. The dose--relaxation curve to isoproterenol was also shifted to the right by droperidol. Propranolol (10(-6) M) failed to significantly alter the dose response curve to dopamine, and in propranolol-treated preparations the antagonism by droperidol of dopamine actions was practically identical with that in control preparations. Droperidol appears to act as a reversible, surmountable antagonist to dopamine actions on dog arterial smooth muscles, and such evidence supports the hypothesis of specific dopamine receptors in dog arteries.


Proficiency in the diagnosis of nonpolypoid colorectal neoplasm yields high adenoma detection rates.
Current efforts to prevent colorectal cancer focus on the detection and removal of neoplasms. Nonpolypoid colorectal neoplasms (NP-CRN) have a subtle appearance that can be difficult to recognize during colonoscopy. Endoscopists must first be familiar with the patterns of NP-CRN in order to detect and diagnose them. We studied the adenoma detection rates of endoscopists who had trained to detect NP-CRN, versus endoscopists who had not. Retrospective Nested Case Control Study. Outpatient Screening Colonoscopy. Adult Veterans. Proficiency in the features and diagnosis of NP-CRN. Adenoma detection. In total, 462 patients had screening colonoscopies-267 by colonoscopists who had trained in the features and diagnosis of NP-CRN. Patient characteristics were similar between groups-the majority were men with a mean age of 62 ± 6 years. Neoplasia was more prevalent (45.7 vs. 34.9%; p = 0.02) in patients evaluated by the trained compared to the conventionally trained group. Trained colonoscopists had a higher adenoma detection rate (0.76 vs. 0.54 adenomas per patient, p < 0.001); removed a higher proportion of neoplasia (77 vs. 35%, p < 0.001); and more frequently diagnosed NP-CRN lesions (OR 2.98, 95% CI: 1.46-6.08) compared to colonoscopists without supplemental training. Endoscopists who are proficient in the detection of NP-CRN had significantly higher adenoma detection rates-of both polypoid and flat adenomas-compared to endoscopists without training, and were more specific in resection of adenomatous over hyperplastic lesions.


An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity.
In worms, as in other organisms, many tissue-specific promoters are sequestered at the nuclear periphery when repressed and shift inward when activated. It has remained unresolved, however, whether the association of facultative heterochromatin with the nuclear periphery, or its release, has functional relevance for cell or tissue integrity. Using ablation of the unique lamin gene in C. elegans, we show that lamin is necessary for the perinuclear positioning of heterochromatin. We then express at low levels in otherwise wild-type worms a lamin carrying a point mutation, Y59C, which in humans is linked to an autosomal-dominant form of Emery-Dreifuss muscular dystrophy. Using embryos and differentiated tissues, we track the subnuclear position of integrated heterochromatic arrays and their expression. In LMN-1 Y59C-expressing worms, we see abnormal retention at the nuclear envelope of a gene array bearing a muscle-specific promoter. This correlates with impaired activation of the array-borne myo-3 promoter and altered expression of a number of muscle-specific genes. However, an equivalent array carrying the intestine-specific pha-4 promoter is expressed normally and shifts inward when activated in gut cells of LMN-1 Y59C worms. Remarkably, adult LMN-1 Y59C animals have selectively perturbed body muscle ultrastructure and reduced muscle function. Lamin helps sequester heterochromatin at the nuclear envelope, and wild-type lamin permits promoter release following tissue-specific activation. A disease-linked point mutation in lamin impairs muscle-specific reorganization of a heterochromatic array during tissue-specific promoter activation in a dominant manner. This dominance and the correlated muscle dysfunction in LMN-1 Y59C worms phenocopies Emery-Dreifuss muscular dystrophy.


The natural prenylated flavone artelastin is an inhibitor of ROS and NO production.
Artelastin, a prenylated flavone previously isolated from Artocarpus elasticus, was evaluated for its effect on the production of reactive oxygen species (ROS) by human polymorphonuclear neutrophils (PMNs) and nitric oxide (NO) by J774 murine macrophage cell line. Artelastin showed to be an inhibitor of ROS production due to a strong O2- scavenging activity. No effect was observed on the activity of myeloperoxidase (MPO). Artelastin showed also to be an inhibitor of NO production without NO scavenging activity. This flavone seems to interfere with the expression of the inducible nitric oxide synthase (iNOS) immediately after LPS-IFNgamma-macrophage stimulation.


Insulin-like growth factor II (IGF-II) and follicle stimulating hormone (FSH) combinations can improve the in vitro development of grown oocytes enclosed in caprine preantral follicles.
Evaluate the possible role of IGF-II alone or in association with FSH on in vitro development of isolated caprine preantral follicles. Preantral follicles (≥150 μm) were isolated from goat ovaries and cultured for 18 days in basic αMEM medium (control) or supplemented with IGF-II alone at 20 or 50 ng/ml, named IGF20 and IGF50, respectively, or in combination with recombinant FSH (FSH, IGF20F or IGF50F). During in vitro culture, the follicles were analyzed by using morphology criteria, antrum formation and growth rate as parameters. After 18 days of follicular culture, oocytes equal to or larger than 110 μm were used for in vitro maturation (IVM). Oocyte viability and meiosis resumption were assessed by fluorescence microscopy after labeling with calcein-AM, ethidium homodimer and Hoechst 33342. The IGF20 treatment was the only treatment capable of maintaining the percentage of morphologically normal follicles from D0 until D6 and from D12 to D18 (p>0.05), while in all other treatments the percentage of morphologically normal follicles decreased progressively during 18 days of in vitro culture (p<0.05). At D18, all treatments with IGF-II or FSH resulted in a significantly higher percentage of normal follicles when compared to αMEM alone. The IGF50F treatment provided a significantly higher early antrum formation rate when compared to αMEM and FSH alone. The addition of IGF-II alone (20 or 50 ng/ml) or in combination with FSH prevented oocyte degeneration after IVM. Moreover, the FSH treatment demonstrated a lower percentage of oocyte degeneration when compared to control (4.35% vs. 26.3%, respectively; p<0.05). Regarding meiosis resumption, the IGF20F treatment was the only treatment that significantly differed from αMEM alone. All treatments except the control (αMEM alone) presented oocytes at metaphase II. IGF-II associated with FSH stimulated in vitro follicular development, oocyte viability and meiotic resumption of caprine oocytes after IVM.


Recent advances in γH2AX biomarker-based genotoxicity assays: A marker of DNA damage and repair.
The phosphorylation of histone variant H2AX and formation of γH2AX is a primary response to the DNA double-strand breaks (DSBs). Detection of γH2AX is a robust and sensitive tool for diagnosis of DNA damage and repair in pre-clinical drug discovery investigations. In addition, the replication stress also leads to the formation of γH2AX and cell death and so γH2AX can serve as a surrogate marker of drug-induced cytotoxicity. Recent advances in genomic research offer an opportunity to detect γH2AX as a specific biomarker for quantitative analysis of DNA damages and repair using high content screening technology and quantitative imaging analysis. The proposed approaches identify a wide range of genetic disorders and are applied in combination with other assays in drug discovery and also for the evaluation of the efficacy of various developmental drugs. In the current review, we provide recent insights into the potential of γH2AX biomarker as a powerful tool in genotoxicity analyses for the monitoring and managing of cancer diseases.


Thromboxane induced red blood cell lysis.
The two thromboxane A2 mimetics, carbocyclic thromboxane A2 (CTA2) and U-46619 (9,11-methanoepoxy PGH2) at concentrations of 400 ng/ml significantly enhanced the release of hemoglobin from both feline and human erythrocyte suspensions. This effect was significantly attenuated by the thromboxane receptor antagonist BM-13,505 indicating that the membrane leakiness is in some way receptor mediated. The effects also appear to be concentration-dependent over the range of 100-400 ng/ml. The membrane labilizing effect of thromboxane analogs is not due to a non-specific eicosanoid effect since iloprost, the stable prostacyclin analog, actually stabilized erythrocyte membranes. Moreover, synthetic thromboxane A2 exerted similar effects to that of the two TxA2-mimetics. This membrane labilizing action of thromboxanes may be important in propagating the other pathophysiologic effects of thromboxane A2 in cardiovascular disease states.


Heterotopic pregnancy following administration of human menopausal gonadotropin and following in vitro fertilization and embryo transfer: two case reports and review of the literature.
We report two cases of heterotopic (combined intra- and extra-uterine) pregnancy in women treated for infertility. In the first case the patient conceived following administration of human menopausal gonadotropin. In the seventh week of gestation she had a spontaneous abortion and in the eighth week required urgent laparotomy for acute abdomen due to the rupture of pregnant right tube. In the second case the patient conceived from IVF-ET; in the eighth week a salpingectomy was made. The intrauterine pregnancy continued regularly until term and the patient was delivered of a healthy baby by caesarean section. We reviewed the literature and we found that heterotopic pregnancy is an insidious disease with a constant increase of incidence, especially in infertile women submitted to therapy for ovulation induction or assisted reproductive techniques. All the patients who have risk factors should be submitted to careful controls in early pregnancy, including an ultrasound transvaginal scan.


Calcium channel blockers in systemic hypertension.
Calcium channel blockers selectively inhibit transmembrane flux of calcium in excitable tissue. Their ability to block calcium-mediated electromechanical coupling in contractile tissue produces peripheral vasodilation and has led to their clinical use in patients with systemic hypertension. The drugs appear to be well tolerated and have excellent safety profiles. Sustained-release preparations allow the drugs to be used once or twice daily. The calcium channel blockers will play an important role in the management of patients with mild, moderate, and severe hypertension when used as monotherapy or when combined with other antihypertensive medications. They can also be used in patients with concomitant diseases, such as angina pectoris and arrhythmia.


Evaluation of white matter microstructure in patients with Parkinson's disease using microscopic fractional anisotropy.
Micro fractional anisotropy (μFA) is more accurate than conventional fractional anisotropy (FA) for assessing microscopic tissue properties and can overcome limitations related to crossing white matter fibres. We compared μFA and FA for evaluating white matter changes in patients with Parkinson's disease (PD). We compared FA and μFA measures between 25 patients with PD and 25 age- and gender-matched healthy controls using tract-based spatial statistics (TBSS) analysis. We also examined potential correlations between changes, revealed by conventional FA or μFA, and disease duration or Unified Parkinson's Disease Rating Scale (UPDRS)-III scores. Compared with healthy controls, patients with PD had significantly reduced μFA values, mainly in the anterior corona radiata (ACR). In the PD group, μFA values (primarily those from the ACR) were significantly negatively correlated with UPDRS-III motor scores. No significant changes or correlations with disease duration or UPDRS-III scores with tissue properties were detected using conventional FA. μFA can evaluate microstructural changes that occur during white matter degeneration in patients with PD and may overcome a key limitation of FA.


Up-regulation of glial cell line-derived neurotrophic factor (GDNF) expression in regenerating muscle fibers in neuromuscular diseases.
Glial cell line-derived neurotrophic factor (GDNF) has been shown to exert a target-derived trophic factor for motor neurons. Immunohistochemical analyses revealed that expression of GDNF in regeneration muscle fibers was up-regulated in polymyositis (PM) and Duchenne type muscular dystrophy (DMD). Reverse transcriptase polymerase chain reaction (RT-PCR) analyses showed that the full length GDNF was up-regulated in PM and DMD muscle; normal muscle exhibited mostly truncated GDNF. The results indicate that the GDNF expression is regulated in regeneration of human skeletal muscle.


Phosphorylation relieves autoinhibition of the kinetochore motor Cenp-E.
During mitosis, chromosome alignment depends on the regulated dynamics of microtubules and on motor protein activities. At the kinetochore, the interplay between microtubule-binding proteins, motors, and kinases is poorly understood. Cenp-E is a kinetochore-associated kinesin involved in chromosome congression, but the mechanism by which this is achieved is unclear. Here, we present a study of the regulation of Cenp-E motility by using purified full-length (FL) Xenopus Cenp-E protein, which demonstrates that FL Cenp-E is a genuine plus-end-directed motor. Furthermore, we find that the Cenp-E tail completely blocks the motility of Cenp-E in vitro. This is achieved through direct interaction between its motor and tail domains. Finally, we show that Cenp-E autoinhibition is reversed by MPS1- or CDK1-cyclin B-mediated phosphorylation of the Cenp-E tail. This suggests a model of dynamic control of Cenp-E motility, and hence chromosome congression, dependent upon phosphorylation at the kinetochore.


Plasma kinetics of a cholesterol-rich emulsion in young, middle-aged, and elderly subjects.
Low density lipoprotein (LDL) plasma concentration is increased in the elderly. In this group, the incidence of coronary artery disease (CAD) is greater and LDL remains an important risk factor for CAD development. In this study, the plasma kinetics of a cholesterol-rich emulsion that binds to LDL receptors was studied in 10-subject groups of the elderly (70 +/- 4 yr), middle-aged (42 +/- 5 yr) and young (23 +/- 2 yr). All were normolipidemic, nonobese, nondiabetic subjects who did not have CAD. The emulsion was labeled with 14C-cholesteryl oleate and injected intravenously into the subjects. Blood samples were drawn at regular intervals over 24 h to determine the plasma decay curve of the emulsion radioactive label and to estimate its plasma fractional clearance rate (FCR, in h(-1)). FCR of the emulsion label was smaller in elderly compared to young subjects (0.032 +/- 0.035 and 0.071 +/- 0.049 h(-1), respectively; mean +/- SD, P< 0.05). FCR of the middle-aged subjects (0.050 +/- 0.071 h(-1)) was intermediate between the values of the elderly and young subjects, although not statistically different from them. A negative correlation was found betweeen the emulsion FCR and subjects' age (r = -0.47, P = 0.008). We conclude that aging is accompanied by progressively diminished clearance of the emulsion cholesterol esters and, by analogy, of the native LDL.


Kinesiophobia contributes to worse functional and patient-reported outcome measures in Achilles tendinopathy: a systematic review.
To assess the effect of kinesiophobia or fear of reinjury on patient-reported outcome measures and physical performance measures in patients with chronic Achilles tendinopathy (AT). Three databases were systematically screened for studies from inception to May 22nd, 2023 for literature investigating the impact of kinesiophobia on PROMs or physical performance metrics in AT. The authors adhered to the PRISMA and R-AMSTAR guidelines as well as the Cochrane Handbook for Systematic Reviews of Interventions. Data on demographics, pain, level of activity, self-reported injury severity, quality of life, single-leg hop performance, and heel-raise performance were recorded. Data was presented primarily in a narrative summary fashion. The MINORS score was used for all studies to perform a quality assessment of included studies. Six studies comprising 705 patients were included in this review. Variations of the Tampa Scale of Kinesiophobia (TSK-11 or TSK-17) were used in all studies. TSK scores were strongly correlated with the Pain Catastrophizing Score (PCS) and Visual Analogue Scale (VAS) scores and were correlated with decreased Victorian Institute of Sports Assessment Achilles (VISA-A) and Foot and Ankle Outcome Scores Quality of Life (FAOS-QoL) subscale scores. Kinesiophobia was associated with heel raise completion with conflicting evidence on correlations with hop test performance. Increased kinesiophobia scores (> 35 points), measured by TSK are associated with worse PROMs, including increased pain, decreased quality of life, increased self-reported severity, and is also associated with poorer physical performance measures in patients with AT. IV.


Are foot orthotics efficacious for treating painful medial compartment knee osteoarthritis? A review of the literature.
This work examined the evidence base concerning the efficacy of laterally wedged foot orthotics for improving the symptomatology associated with painful disabling osteoarthritis of the knee medial compartment. To this end, all relevant peer-reviewed publications on this topic published in the English language were retrieved and analysed. In addition, related biomechanical publications were analysed. These data indicate a strong scientific basis for applying wedged insoles in attempts to reduce osteoarthritic pain of biomechanical origin. Further research to substantiate their efficacy in well-designed clinical trials seems warranted.


Using medical storytelling to communicate problems and solutions in the low back pain conundrum: an evidence-based tale of twins.
Low back pain (LBP) is the number one cause of disability world-wide. It is also the most expensive area in healthcare. Patient-centered innovations are needed. This paper uses medical storytelling to illustrate the common problems that often lead to unnecessary suffering for patients, and costs to society. We present innovative solutions, including narrative interventions. We use medical storytelling to present a scenario in which hypothetical twin patients with identical LBP episodes enter the healthcare system, with one twin managed in an appropriate manner, and the other inappropriately. One twin becomes a chronic LBP sufferer, while the other experiences quick resolution, despite identical conditions. Recommendations are made to de-implement inappropriate action and to implement a more productive approach. Many patients with LBP descend into chronic pain. This is rarely inevitable based on clinical factors. Much of chronic LBP results from how the condition is handled within the healthcare system. Medical narrative may be one innovation to illustrate the problem of current LBP management, recommend solutions and foster changes in clinical behavior. The starkly different outcomes for each identical twin are illustrated. Recommendations are made for reframing the situation to de-implement the inappropriate and to implement a more appropriate approach.


Cooperative Bimetallic Catalysis via One-Metal/Two-Ligands: Mechanistic Insights of Polyfluoroarylation-Allylation of Diazo Compounds.
Metal/ligand in situ assembly is crucial for tailoring the reactivity & selectivity in transition metal catalysis. Cooperative catalysis via a single metal/two ligands is still underdeveloped, since it is rather challenging to harness the distinct reactivity profiles of the species generated by self-assembly of a single metal precursor with a mixture of different ligands. Herein, we report a catalytic system composed of a single metal/two ligands for a three-component reaction of polyfluoroarene, α-diazo ester, and allylic electrophile, leading to highly efficient construction of densely functionalized quaternary carbon centers, that are otherwise hardly accessible. Mechanistic studies suggest this reaction follows a cooperative bimetallic pathway via two catalysts with distinct reactivity profiles, which are assembled in situ from a single metal precursor and two ligands and work in concert to escort the transformation.


HOX family transcription factors: Related signaling pathways and post-translational modifications in cancer.
HOX family transcription factors belong to a highly conserved subgroup of the homeobox superfamily that determines cellular fates in embryonic morphogenesis and the maintenance of adult tissue architecture. HOX family transcription factors play key roles in numerous cellular processes including cell growth, differentiation, apoptosis, motility, and angiogenesis. As tumor promoters or suppressors HOX family members have been reported to be closely related with a variety of cancers. They closely regulate tumor initiation and growth, invasion and metastasis, angiogenesis, anti-cancer drug resistance and stem cell origin. Here, we firstly described the pivotal roles of HOX transcription factors in tumorigenesis. Then, we summarized the main signaling pathways regulated by HOX transcription factors, including Wnt/β-catenin, transforming growth factor β, mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and nuclear factor-κB signalings. Finally, we outlined the important post-translational modifications of HOX transcription factors and their regulation in cancers. Future research directions on the HOX transcription factors are also discussed.


Hearing the Voices of Wingless Angels: A Critical Content Analysis of Nurses' COVID-19 Experiences.
The world has been affected by an outbreak of the novel coronavirus (COVID-19). Health care workers are among those most at risk of contracting the virus. In the fight against the coronavirus, nurses play a critical role. Still, most social media platforms demonstrate that nurses fear that their health is not being prioritized. The purpose of this study is to investigate nurses' experiences through analyzing the main themes shared on Instagram by nurses during the COVID-19 pandemic. In contrast with highly structured research, the current paper highlights nurses' natural language use in describing their experiences during the first months of the outbreak in their workplace. Instagram captions were utilized as a data source. Leximancer was utilized for the content analysis of nurses' narratives towards their coronavirus experience. We sought to accomplish three research objectives: the first was to identify the main themes in the descriptions of nurses' experiences shared via their social media, specifically Instagram; then, to determine the relationships among concepts, and finally, to give useful implications based on the findings. The current study uses a qualitative (i.e., narratives) approach to analyze the main components of the nurses' experiences during the pandemic. The Leximancer software analysis revealed nine major textual themes and the relationships among these themes. In order of the relative importance, the themes were "patients", "coronavirus", "exhaustion", "family", "hospital", "personal protective equipment" (PPE), "shift", "fear", and "uncertainty". The results offer practical implications based on the social media information regarding nurses' overall experiences.


Role of G protein-coupled receptor kinase 2 and arrestins in beta-adrenergic receptor internalization.
G protein-coupled receptors (GPCRs) mediate the action of messengers that are key modulators of the function, growth, and differentiation of cardiac and vascular cells. A general feature of GPCRs is the existence of complex regulatory mechanisms that modulate receptor responsiveness and underlie important physiologic phenomena such as signal integration and desensitization. The molecular mechanisms of desensitization have been investigated with the beta2-adrenergic receptor (beta2AR) used as the main model system. Rapid regulation of betaAR and other GPCRs appears to involve agonist-promoted receptor phosphorylation by G protein-coupled receptor kinases (GRKs). This is followed by binding of uncoupling proteins termed arrestins and transient receptor internalization, which plays a key role in resensitizing GPCR by allowing its dephosphorylation and recycling. Recent data indicate that, besides the uncoupling function, GRK2 and beta-arrestin also directly participate in beta2AR sequestration, thus providing the trigger for its resensitization. A detailed knowledge of the role of GRKs and arrestins in betaAR internalization would make their physiologic role in the modulation of cellular responses to messengers better understood.


Does joint-sparing tumor resection jeopardize oncologic and functional outcomes in non-metastatic high-grade osteosarcoma around the knee?
We previously reported joint-sparing tumor resection for osteosarcoma with epiphyseal involvement in which transepiphyseal osteotomy went through the in situ ablated epiphysis. However, we do not know whether this is a safe approach when compared with joint-sacrificed tumor resection. Our objective was to compare oncologic and functional outcomes between patients who underwent joint preservation (JP) and joint replacement (JR) tumor resection. Furthermore, we identified the risk factors of local recurrence, metastasis and survival. Eighty-nine patients with non-metastatic high-grade osteosarcoma around the knee were treated with limb-salvage surgery (JP in 47 and JR in 42). Age, gender, tumor location, pathologic fracture, plain radiographic pattern, limb diameter change, perivascular space alteration, surgical margin, local recurrence, metastasis, death, and the Musculoskeletal Tumor Society (MSTS)-93 scores were extracted from the records. Univariate analysis was performed to compare oncologic and functional outcomes. Binary logistic and cox regression models were used to identify predicted factors for local recurrence, metastasis, and survival. Local recurrence, metastasis and overall survival were similar in the JP and JR group (p = 0.3; p = 0.211; p = 0.143). Major complications and limb survival were also similar in the JR and JP group (p = 0.14; p = 0.181). The MSTS score of 27.06 ± 1.77 in the JP group was higher than that of 25.88 ± 1.79 in the JR group (p = 0.005). The marginal margin of soft tissue compared with a wide margin was the only independent predictor of local recurrence (p = 0.006). Limb diameter increase and perivascular fat plane disappearance during neoadjuvant chemotherapy were independent predictors for metastasis (p = 0.002; p = 0.000) and worse survival (p = 0.000; p = 0.001). Joint-sparing tumor resection with the ablative bone margin offers advantage of native joint preservation with favorable functional outcomes while not jeopardizing oncologic outcomes compared with joint-sacrificed tumor resection. Surgeon should strive to obtain adequate soft tissue surgical margin decreasing risk of local recurrence. Novel drug regimens might be reasonable options for patients with obvious limb diameter increase and perivascular fat disappearance during chemotherapy.


Dietary obesity: effects of drugs on food intake in S 5B/P1 and Osborne-Mendel rats.
The effect of several drugs on food intake has been examined in two strains of rats, one (S 5B/P1) which is resistant to developing obesity when eating a high fat diet, and one (Osborne-Mendel) which readily develops obesity when eating the same diet. Insulin and 2-deoxy-D-glucose increased food intake in a dose dependent manner in both S 5B/P1 and Osborne-Mendel rats. However, the S 5B/P1 rats showed a greater response, with a shorter latency period, to both agents than did the Osborne-Mendel rats. Conversely, d-amphetamine at the higher doses produced a dose dependent suppression of food intake with maximal suppression being similar for both strains. At a lower dose, however, d-amphetamine significantly increased food intake in the Osborne-Mendel rats, but not in the S 5B/P1 rats. The S 5B/P1 rats were also slightly more sensitive to the anorexic effects of lower dose adenosine than were the Osborne-Mendel rats whereas the reverse was true following higher dose adenosine. Naloxone suppressed food intake equally in both strains and D-glucose did not alter food intake in either strain. These studies identify three drugs, all stimulatory, to which the two strains of rat respond differently.


Investigation of selenium nutritional status and dietary pattern among children in Kashin-Beck disease endemic areas in Shaanxi Province, China using duplicate portion sampling method.
Selenium deficiency is a primary risk factor of Kashin-Beck disease (KBD). This study aimed to investigate whether children in endemic areas could maintain sufficient selenium intake after termination of selenium supplement administration, and evaluate their comprehensive nutritional status and dietary structure. Duplicate portion sampling combined with a questionnaire was adopted to collect data on categories and quantity of all food ingested in three consecutive days. Occipital hair was also collected to detect selenium content by hydride generation atomic fluorescence spectrometry (HGAFS). CDGSS3.0 software and factor analysis were integrated to assess the children's comprehensive nutritional status and dietary structure. This study included 240 sex-matched (1:1) children aged 7-12 years from KBD endemic (n = 120) and non-endemic (n = 120) areas. Overall, 720 solid food, 720 liquid, and 240 hair samples were collected for selenium determination. The mean selenium level in hair of children in endemic areas (0.38 ± 0.16 mg/kg) was significantly lower than that in children in non-endemic areas (0.56 ± 0.28 mg/kg, Z = -5.249, p < 0.001). The dietary selenium intake of children in endemic areas was 40.0% lower than that in children in non-endemic areas (Z = -9.374, p < 0.001). Children in endemic areas consumed significantly less diverse dietary items leading to significantly less intake of multiple nutrients compared to children in non-endemic areas. The dietary selenium intake of most children in endemic areas was less than the recommended amount. The dietary structure of children was undiversified, which limited the intake of multiple nutrients. Therefore, comprehensive nutrition rather than sole selenium intake should be the primary concern in the future.


Congenital atresia and stenosis of the duodenum: the impact of a prenatal diagnosis.
This review was undertaken to determine the effects of prenatal diagnosis, on the basis of ultrasonographic evidence, of a duodenal obstruction on the care and morbidity of the newborn infant. The records of 46 cases of either atresia or stenosis of the small bowel in infants treated during the last six years in a tertiary perinatal center were reviewed retrospectively. A prenatal fetal diagnosis of obstruction was made in 13 patients (12 obstructions located in the duodenum and one in the jejunum). The mean gestational age at prenatal diagnosis was 33.7 weeks (range 27 to 37 weeks). The course of those infants with the prenatal diagnosis made by ultrasound was compared with that of those infants in whom the diagnosis was established after the onset of symptoms of obstruction appeared. Such a prenatal diagnosis resulted in earlier surgical intervention (1.8 versus 3.9 days). Metabolic complications secondary to repeated vomiting were found to be less frequent. The expectant mother in whom such a fetal prenatal diagnosis has been made can be transported to a tertiary level perinatal center where neonatal and specialized surgical expertise are available. After birth, the infant can undergo immediate operation without being separated from its mother.


Local influence for the subdistribution of a competing risk.
Local influence measures have been shown to be a useful tool in identifying influential individuals, and assessing model behaviour towards small perturbations. In the setting of competing risks, we developed a measure of local influence for the Fine and Gray model for the subdistribution hazard. The plot of local influence showed some relationship with time failure rank. This was illustrated on a real data set from a randomized clinical trial in acute promyelocytic leukaemia and on a simulation study.


Earthworms reduce the dissemination potential of antibiotic resistance genes by changing bacterial co-occurrence patterns in soil.
Globally distributed earthworms affect compositions of soil compounds, microbial community structures, as well as antibiotic resistance genes (ARGs). Compared to their surroundings, earthworm gut is a simpler environment which could filter out microbes when soil passes through it. However, little is known about how earthworms affect the dissemination of ARGs in soil, and the understanding of the relationship between microbe-microbe interactions and ARGs is still lacking. Here, we designed a microcosm experiment with earthworm addition, and determined bacterial and fungal community compositions based on amplicon sequencing. We also examined mobile genetic elements (MGEs) and ARGs in earthworm gut and soils using high-throughput qPCR. The results showed significant differences of bacterial, fungal and ARG patterns between gut and soil. Earthworms indirectly impacted the patterns of ARGs in soils by affecting bacterial communities and soil properties, which play key roles in the distribution of ARGs and MGEs. The absolute abundances of MGEs in earthworm gut were significantly lower than those in soils, and earthworms reduce the absolute abundance of MGEs in soils. Earthworms changed the microbial co-occurrence patterns, and reduced bacterial connectivity, which were significantly and positively correlated with MGE abundance. These results highlight the importance of earthworm on the distribution and dissemination of ARGs in soils.


Socioecological diversity and inclusion: a framework for advancing diversity science.
Understanding environmental influences on group processes has been a foundational goal of groups research since its inception. The aim of this paper is to synthesize recent research on the social ecology of diversity and inclusion. In doing so, we suggest a socioecological framework for examining how facets of the natural and social environment shape important intragroup and intergroup outcomes. Socioecological diversity reflects the distribution of social groups within a particular environment, including demographic composition, relative representation, and segregation. Socioecological inclusion refers to cues embedded in the environment that signal a social group's inclusion or exclusion in a given setting. These include cues embedded in the physical environment (physical cues), political environment (policies, practices, and rhetoric), and social environment (aggregated attitudes).


Blood DHEAS concentrations correlate with cognitive function in chronic schizophrenia patients: a pilot study.
There is evidence that neurosteroids such as DHEA and its sulfated form DHEAS can modulate cognitive function. We hypothesize that DHEA/S concentrations may be linked to cognitive impairment in schizophrenia. The aim of this pilot study was to test this hypothesis by examining the relationship between blood levels of DHEAS and cognitive function. The performance of 26 stable medicated chronic schizophrenia patients in a range of neuropsychological domains including verbal memory (Wechsler Memory Scale), executive function (AIM), memory of faces (PFMT), memory for objects (VOLT) and identification of facial emotional expressions (PEAT) was assessed. Single morning blood samples were assayed for levels of DHEAS and cortisol. Significant associations were found between DHEAS levels and DHEAS/Cortisol ratio and verbal memory, executive function and memory for faces. The relationship was independent of the age related reduction in DHEAS levels. These preliminary results suggest that DHEAS may be associated with cognitive impairment in schizophrenia.


Older Women who are Overweight or Obese Have Vertebral Abnormalities, Partially Degraded TBS, and BMD that Worsen with Weight Loss.
Obesity is a risk factor for chronic diseases and moderate weight loss is generally recommended. Energy restriction results in the loss of hip bone mineral density (BMD) in older adults, but there is no consistent decline at the lumbar spine (LS), possibly due to vertebral abnormalities although this may also be dependent on the amount of weight loss. In this secondary analysis of weight loss trials investigating BMD and trabecular bone score (TBS) changes over 12-18 months, 92 postmenopausal women (60.8 ± 5.8 years; body mass index 32.7 ± 4.4 kg/m2) without osteoporosis, were divided into two groups: those who lost < 5% body weight (minimal) or ≥ 5% (moderate). Hip and LS-BMD and TBS were measured at baseline, 6 and 12-18 months. Exclusion of vertebral abnormalities (VE) was used to calculate BMD at the spine (LS-BMD-VE) using standard guidelines. Women lost 2.3 ± 2.4% and 8.5 ± 4.7% weight in the minimal and moderate weight loss groups, respectively. Over one third of the women had at least one vertebral abnormality or partially degraded TBS at baseline that worsened after weight loss, increasing to over 50% in this population (p < 0.05). TBS and hip BMD decreased with weight loss (p < 0.05), but LS-BMD did not decrease significantly. However, after excluding vertebral abnormalities, the LS-BMD-VE decreased in the entire population (p < 0.01), and by 1.7 ± 4.3% in the moderate weight loss group. This study suggests that older women without osteoporosis have vertebral abnormalities that obfuscated declines in BMD with weight loss, indicating that bone at the spine is further compromised.


Evaluation of malignancy of hepatocellular carcinoma using the ultrasonic B-mode method: clinical significance of extracapsular invasion of hepatocellular carcinoma using ultrasonography.
To determine the influence of capsule formation or presence of capsular invasion on the prognosis of hepatocellular carcinoma (HCC) patients. The patient group consisted of 70 patients with 74 HCC lesions who had been examined by US and undergone surgical tumor resection at our institution. For these patients, we conducted the following comparative studies: (a) comparison between halo findings on US and microscopic capsular results; (b) comparison between halo findings on US and tumor diameter, tumor histological differentiation, and serum value of each tumor marker; and (c) comparison between halo findings on US and tumor recurrence. (a) The corresponding value between sonographic halo and histological capsule was 90.1%, and that between presence of extracapsular invasion on US and that seen by histology was 88.0%. (b) There was no relation between US images and histological differentiation of tumors. (c) Presence of extracapsular invasion on US was a predisposing factor for the development of tumor recurrence. (1) Globally speaking, sonographic halo corresponded to the histological tumor capsule. (2) In patients with extracapsular invasion, tumor recurrence after treatment increased. Thus, a better understanding of sonographic halo findings helps determine diagnostic and therapeutic strategies in HCC patients.


Role of water in the energy of hydrolysis of phosphoanhydride and phosphoester bonds.
The observed equilibrium constants for hydrolysis (Kobs) of a phosphoester and a phosphoanhydride bond were measured under a variety of conditions likely to alter the interactions of reactants and products with water. These included increasing the pH of the medium from 5.0 to 10.0, increasing the MgCl2 concentration form 0 to 200 mM, and decreasing the water activity of the medium by adding either dimethyl sulfoxide (50%, v/v) or polyethylene glycol 6,000-8,000 (50%, w/v). The Kobs for phosphoesters such as phosphoserine, glucose phosphate, glycerol phosphate, and ethylene glycol phosphate varied little over this wide range of conditions, the extreme values of Kobs being 12 and 200 M. In contrast, the Kobs for the phosphoanhydride bond of pyrophosphate varied from a value greater than 20,000 to 0.1 M. In totally aqueous media at a pH between 7.0 and 8.0 and in the presence of 0.5-1.0 mM MgCl2, the energy of hydrolysis of pyrophosphate was 1.2-4.0 kcal/mol greater than that of phosphoserine. However, when the water activity was decreased by adding polyethylene glycol to the medium within the same pH and MgCl2 concentration range, the energy of hydrolysis of phosphoserine became 2.0-2.5 kcal/mol greater than that of pyrophosphate. The results suggest that for phosphoesters, the solvation energies of reactants and products, unlike the case of phosphoanhydride bonds, are not the major factors in determining the energy of hydrolysis.


Triterpenoids from the roots of Rhaphiolepis indica var. tashiroi and their anti-inflammatory activity.
Two new triterpenoids, 2α,3β-dihydroxyolean-11,13(18)-dien-19β,28-olide (1) and 3β,5β-dihydroxyglutinol (2), together with eight known compounds (3-10) were isolated from the roots of Rhaphiolepis indica var. tashiroi (Rosaceae). The structures of 1-10 were determined by spectroscopic techniques. Among these isolates, 2α,3β-dihydroxyolean-13(18)-en-28-oic acid (9) exhibited inhibitory effect on N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide production, with an IC50 value of 16.50 μM.


Chlorine and bromine isotope fractionation of halogenated organic pollutants on gas chromatography columns.
Compound-specific chlorine/bromine isotope analysis (CSIA-Cl/Br) has become a powerful approach to investigate degradation pathways and apportion sources of halogenated organic pollutants (HOPs) in the environment. CSIA-Cl/Br is usually conducted by gas chromatography-mass spectrometry (GC-MS), which could be negatively impacted by isotope fractionation on GC columns. In this study, on-column Cl/Br isotope fractionation of 31 organochlorines and 4 organobromines was explored using GC-double focus magnetic-sector high resolution MS (GC-DFS-HRMS). Twenty-nine HOPs exhibited inverse Cl/Br isotope fractionation for which the heavier isotopologues eluted faster than the lighter ones on GC columns, and two polychlorinated biphenyls (PCB-138 and PCB-153) showed normal isotope fractionation, whereas the rest four HOPs did not show observable isotope fractionation. The isotope fractionation extents varied from -13.0‰ to 73.1‰. Mechanisms of the on-column Cl/Br isotope fractionation were tentatively elucidated with a modified two-film model. The results demonstrate that integrating peak area as complete as possible for separable chromatographic peaks and integrating the middle retention-time segments for the inseparable peaks are helpful to improve precision and accuracy of the CSIA-Cl/Br data. The findings of this study will shed light on development of CSIA-Cl/Br methods with respect to improving precision and accuracy.


Experience and Utility of the Protocol Kidney Biopsy in the First Year of Kidney Transplantation.
Protocol kidney biopsy (PKB) in kidney transplant is a useful tool for graft monitoring because the subclinical detection of histologic lesions helps to modulate immunosuppression. We analyze our experience. We performed a descriptive study that analyzed the PKB results at the fourth to sixth month and the first year post transplant of patients with kidney transplant followed in our hospital between January 2015 and June 2021. A total of 100 patients and 134 biopsy results were included, of which 71 were obtained between the fourth and sixth month and 63 at the first year. The mean age was 57.8 years, and 66% were men. Unknown etiology was the most common underlying kidney disease (31%), followed by diabetes mellitus (15%) and polycystic kidney disease (14%). A total of 80% had panel-reactive antibody < 50%. Induction therapy consisted of thymoglobulin (51%) and basiliximab (49%), and maintenance therapy consisted of corticosteroids and tacrolimus (100%), mycophenolate mofetil (82%), and mammalian target of rapamycin inhibitor (18%). Of the total of the PKB results (n = 134), 19 episodes of subclinical rejection (14%) and 10 with borderline changes (7.4%) were observed. Regarding other findings, there were cases of nephrocalcinosis (4.4%), immunoglobulin A nephropathy (2.2%), and BK nephropathy (1.5%). The PKB brought about a change in the therapeutic attitude in 45 cases (33%) of the total number of biopsies, the most frequent change being the administration of boluses of methylprednisolone (12.6%) and the change to mammalian target of rapamycin inhibitor (8.9%). In our experience, PKB is a useful tool for monitoring and evaluating histologic changes without clinical expression in the kidney graft, allowing us to adapt the treatment during the first year of kidney transplant.


[Ni30S16(PEt3)11]: an open-shell nickel sulfide nanocluster with a "metal-like" core.
Reaction of [Ni(1,5-cod)2] (30 equiv.) with PEt3 (46 equiv.) and S8 (1.9 equiv.) in toluene, followed by heating at 115 °C for 16 h, results in the formation of the atomically precise nanocluster (APNC), [Ni30S16(PEt3)11] (1), in 14% isolated yield. Complex 1 represents the largest open-shell Ni APNC yet isolated. In the solid state, 1 features a compact "metal-like" core indicative of a high degree of Ni-Ni bonding. Additionally, SQUID magnetometry suggests that 1 possesses a manifold of closely-spaced electronic states near the HOMO-LUMO gap. In situ monitoring by ESI-MS and 31P{1H} NMR spectroscopy reveal that 1 forms via the intermediacy of smaller APNCs, including [Ni8S5(PEt3)7] and [Ni26S14(PEt3)10] (2). The latter APNC was also characterized by X-ray crystallography and features a nearly identical core structure to that found in 1. This work demonstrates that large APNCs with a high degree of metal-metal bonding are isolable for nickel, and not just the noble metals.


Visible-Light-Enabled Enantioconvergent Synthesis of α-Amino Acid Derivatives via Synergistic Brønsted Acid/Photoredox Catalysis.
An unprecedented radical cross-coupling reaction was achieved between glycine esters and racemic α-bromoketones catalyzed by synergistic Brønsted acid/photoredox catalysis, thus serving as an efficient platform for the synthesis of highly valuable enantioenriched unnatural α-amino acid derivatives. This dual catalysis provides a powerful capability to control the reactive radical intermediate and iminium ion, thereby enabling enantioconvergent bond-formation in a highly stereochemical manner. An array of valuable enantioenriched unnatural α-amino acid derivatives bearing two contiguous stereogenic centers are readily accessible with high diastereoselectivity and excellent enantioselectivity, which include α-amino acids with a unique β-fluorinated quaternary stereocenter or its β-all-carbon counterpart. A strong chiral amplification effect was observed in this dual catalytic system.