Family planning inDaphnia: resistance to starvation in offspring born to mothers grown at different food levels.
We observed a shift in maternal investment per offspring in clonal cultures of twoDaphnia species. Mothers grown at high food levels produced large clutches of smaller eggs but their offspring could not survive long under starvation conditions. Genetically identical mothers grown at low food levels produced small cultches of larger eggs, and their offspring, albeit low in numbers, were able to survive long periods of starvation. Our data show thatDaphnia mothers are capable of assessing food level and use this information in adjusting their fractional peroffspring allocation of reproductive resources.


Post-acute sequelae of COVID-19 in adults referred to COVID recovery clinic services in an integrated health system in Texas.
The epidemiology and organ-specific sequelae following acute illness due to COVID-19 and prompting patients to seek COVID recovery care are not yet well characterized. This cross-sectional study reviewed data on 200 adult patients with prolonged symptoms of COVID-19 (>14 days after symptom onset) not resolved by usual primary care or specialist care who were referred for COVID-specific follow-up. Most patients sought COVID recovery clinic visits within the first 2 months of initial onset of symptoms (median 37 days), with some seeking care for sequelae persisting up to 10 months (median 82 days). At the time of telehealth evaluation, 13% of patients were using home oxygen, and 10% of patients had been unable to return to work due to persistent fatigue and/or subjective cognitive dysfunction ("brain fog"). The prominent specific symptom sequelae prompting patients to seek COVID-specific evaluation beyond usual primary care and specialist referrals were dyspnea, fatigue/weakness, and subjective cognitive dysfunction, irrespective of whether patients had required hospitalization or time since COVID-19 symptom onset.


Ganodermin, an antifungal protein from fruiting bodies of the medicinal mushroom Ganoderma lucidum.
A 15-kDa antifungal protein, designated ganodermin, was isolated from the medical mushroom Ganoderma lucidum. The isolation procedure utilized chromatography on DEAE-cellulose, Affi-gel blue gel, CM-Sepharose and Superdex 75. Ganodermin was unadsorbed on DEAE-cellulose and adsorbed on Affi-gel blue gel and CM-Sepharose. Ganodermin inhibited the mycelial growth of Botrytis cinerea, Fusarium oxysporum and Physalospora piricola with an IC50 value of 15.2 microM, 12.4 microM and 18.1 microM, respectively. It was devoid of hemagglutinating, deoxyribonuclease, ribonuclease and protease inhibitory activities.


Characterising the grey matter correlates of leukoaraiosis in cerebral small vessel disease.
Cerebral small vessel disease (SVD) is a heterogeneous group of pathological disorders that affect the small vessels of the brain and are an important cause of cognitive impairment. The ischaemic consequences of this disease can be detected using MRI, and include white matter hyperintensities (WMH), lacunar infarcts and microhaemorrhages. The relationship between SVD disease severity, as defined by WMH volume, in sporadic age-related SVD and cortical thickness has not been well defined. However, regional cortical thickness change would be expected due to associated phenomena such as underlying ischaemic white matter damage, and the observation that widespread cortical thinning is observed in the related genetic condition CADASIL (Righart et al., 2013). Using MRI data, we have developed a semi-automated processing pipeline for the anatomical analysis of individuals with cerebral small vessel disease and applied it cross-sectionally to 121 subjects diagnosed with this condition. Using a novel combined automated white matter lesion segmentation algorithm and lesion repair step, highly accurate warping to a group average template was achieved. The volume of white matter affected by WMH was calculated, and used as a covariate of interest in a voxel-based morphometry and voxel-based cortical thickness analysis. Additionally, Gaussian Process Regression (GPR) was used to assess if the severity of SVD, measured by WMH volume, could be predicted from the morphometry and cortical thickness measures. We found significant (Family Wise Error corrected p < 0.05) volumetric decline with increasing lesion load predominately in the parietal lobes, anterior insula and caudate nuclei bilaterally. Widespread significant cortical thinning was found bilaterally in the dorsolateral prefrontal, parietal and posterio-superior temporal cortices. These represent distinctive patterns of cortical thinning and volumetric reduction compared to ageing effects in the same cohort, which exhibited greater changes in the occipital and sensorimotor cortices. Using GPR, the absolute WMH volume could be significantly estimated from the grey matter density and cortical thickness maps (Pearson's coefficients 0.80 and 0.75 respectively). We demonstrate that SVD severity is associated with regional cortical thinning. Furthermore a quantitative measure of SVD severity (WMH volume) can be predicted from grey matter measures, supporting an association between white and grey matter damage. The pattern of cortical thinning and volumetric decline is distinctive for SVD severity compared to ageing. These results, taken together, suggest that there is a phenotypic pattern of atrophy associated with SVD severity.


Radical-induced metal-free alkynylation of aldehydes by direct C-H activation.
A direct C(sp(2) )H alkynylation of aldehyde C(O)H bonds with hypervalent iodine alkynylation reagents provides ynones under metal-free conditions. In this method, 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-EBX) constitutes an efficient alkynylation reagent for the introduction of the triple bond. The substrate scope is extended to a variety of (hetero)aromatic, aliphatic, and α,β-unsaturated aldehydes.


QT dispersion and risk factors for sudden cardiac death in patients with hypertrophic cardiomyopathy.
This study examines the relation of QT dispersion (QTd) on a surface electrocardiogram (ECG) to clinical features and established risk factors of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HC). One hundred fifty-six consecutive patients with HC (91 men, mean age 41+/-15 years, range 7 to 79) and 72 normal subjects (41 men, mean age 39+/-9 years, range 20 to 60) were studied. Standard 12-lead ECGs were recorded from each subject using a MAC VU electrocardiograph. Patients with nonsinus rhythm, atrioventricular conduction block, QRS duration > 120 ms, age < 15 years, and low amplitude T waves were excluded from the analysis (n=51). Another 22 patients who were receiving amiodarone and/or sotalol therapy were also excluded. QT interval and QTd were measured using automated analysis in the remaining 83 patients (46 men, age 40+/-14 years, range 16 to 76). QT interval (406+/-38 ms), QTc interval (432+/-27 ms), and QTd (43+/-25 ms) were significantly greater in patients with HC than in normal controls (386+/-31 ms, 404+/-16 ms, 26+/-16 ms, respectively) (p <0.0001). QTd was significantly greater in patients with HC with chest pain compared with asymptomatic or mildly symptomatic patients (50+/-28 ms vs 37+/-20 ms, p=0.02). Increased QTd was found in patients with dyspnea New York Heart Association functional classes II/III than in those with dyspnea New York Heart Association functional class I (50+/-27 ms vs 38+/-22 ms, p=0.04). QTd was weakly correlated with maximum left ventricular wall thickness (r=0.228, p=0.038). No significant association was found between QTd and any risk factors for SCD. Thus, patients with HC have increased QTd. The QTd correlates with symptomatic status. Assessment of QTd might provide complementary clinical characterization of patients with HC but its relation to SCD remains uncertain.


Whole blood serotonin and tryptophan in autism: temporal stability and the effects of medication.
Whole blood serotonin (5-HT) was significantly increased in a drug-free autistic group (n = 17) compared to age- and sex-matched normal control (n = 20). Blood tryptophan (TRP) values and platelet counts were similar in unmedicated autistics and normal subjects; but whole blood concentrations of TRP were significantly lower, and 5-HT values tended to be lower in the medicated group compared to unmedicated autistics. Highly significant intraclass correlation coefficients and low mean percentage differences were found for repeated measures over a year's period of whole blood 5-HT and the platelet count in the unmedicated but not in the medicated group. Blood TRP values were highly variable over time in both the medicated and drug-free autistic groups.


Effect of Wearing Different Masks on Acoustic, Aerodynamic, and Formant Parameters.
This study aimed to investigate the effects of different types of masks on acoustic, aerodynamic, and formant parameters in healthy people. Our study involved 30 healthy participants, 15 of each gender, aged 20-40 years. The tests were conducted under four conditions: without a mask, after wearing a surgical mask, after wearing a head-mounted N95 mask, and after wearing an ear-mounted N95 mask. Voice recording was done with the mask on. The acoustic parameters include mean fundamental frequency (F0), mean intensity, percentage of jitter (local), percentage of shimmer (local), mean noise to harmonic ratio (NHR), aerodynamic parameter, maximum phonation time (MPT), and formant parameters (/a/, /i/, /u/ three vowels F1, F2). The main effect of mask type was significant in MPT, mean F0, mean HNR, /a/F1, /a/F2, /i/F2. However, the effect sizes and power in /a/F2, /i/F2 were low. MPT, mean F0 and mean HNR significantly increased and /a/F1 significantly decreased after wearing the head-mounted n95 mask. The mean F0 and mean HNR increased significantly after wearing the ear-mounted n95 mask. No significant changes were observed in parameters after wearing the surgical mask in this study. When the statistics are performed separately for males and females, the results obtained are similar to those previously obtained for unspecified males and females. After wearing the surgical mask, this study found insignificant changes in mean F0, jitter (local), shimmer (local), mean NHR, mean intensity, MPT, and the vowels F1 and F2. This may be due to the looser design of the surgical mask and the relatively small attenuation of sound. N95 masks have a greater effect on vocalization than surgical masks and may cause changes in F0 and HNR after wearing an N95 mask. In the present study, no significant changes in jitter and shimmer were observed after wearing the mask. In addition, there was a significant reduction in /a/F1 after wearing the N95 headgear mask may owing to its high restriction of jaw mobility. In future studies, the change in jaw movement amplitude after wearing the mouthpiece can be added to investigate.


Monitoring transfusionist practices: a strategy for improving transfusion safety.
Data from New York State indicate that about 1 of every 33,000 red cell units transfused is ABO-incompatible with the recipient. National application of these data suggests that as many as 360 ABO-incompatible whole blood and red cell transfusions might occur annually in the United States. Phlebotomy and blood bank laboratory errors cause some of these ABO-incompatible transfusions, but the greatest number result either partially or solely from the failure of transfusionists to identify properly either a patient or the blood component a patient receives. A quality assessment/quality improvement (QA/QI), process is described that allowed for the direct oversight (monitoring) of transfusionists' practices and for the assessment of institutional policies for blood administration. At the beginning of the QA/QI process, monitoring of blood administration practices revealed that a variance from institutional blood administration policy occurred during 50 percent of blood and component transfusions. As a result of the QA/QI process, the percentage of transfusions with an associated variance from institutional policy dropped to nearly zero. The QA/QI process described in this report, or one similar to it, could improve transfusion safety and serve as a model for increased involvement by transfusion service medical directors in the oversight of transfusionists' practices.


Mercury-resistant rhizobial bacteria isolated from nodules of leguminous plants growing in high Hg-contaminated soils.
A survey of symbiotic bacteria from legumes grown in high mercury-contaminated soils (Almadén, Spain) was performed to produce a collection of rhizobia which could be well adapted to the environmental conditions of this region and be used for restoration practices. Nineteen Hg-tolerant rhizobia were isolated from nodules of 11 legume species (of the genera Medicago, Trifolium, Vicia, Lupinus, Phaseolus, and Retama) and characterized. Based on their growth on Hg-supplemented media, the isolates were classified into three susceptibility groups. The minimum inhibitory concentrations (MICs) and the effective concentrations that produce 50% mortality identified the patterns of mercury tolerance and showed that 15 isolates were tolerant. The dynamics of cell growth during incubation with mercury showed that five isolates were unaffected by exposure to Hg concentrations under the MICs. Genetic analyses of the 16S rRNA gene assigned ten strains to Rhizobium leguminosarum, six to Ensifer medicae, two to Bradyrhizobium canariense, and one to Rhizobium radiobacter. Inoculation of host plants and analysis of the nodC genes revealed that most of them were symbiotically effective. Finally, three isolates were selected for bioremediation processes with restoration purposes on the basis of their levels of Hg tolerance, their response to high concentrations of this heavy metal, and their genetic affiliation and nodulation capacity.


Inhibition of lipid peroxide decomposition by compounds which bind with cytochrome p-450.
The kinetics of lipid peroxide decomposition catalysed by microsomal enzymes and inhibited by SKF-525 A, hexobarbital, phenobarbital and aniline were investigated. The results indicate that the in vitro interaction of hexobarbital and SKF-525 A (type I binding compounds) with microsomal cytochrome p-450 inhibits the peroxidase activity while the in vitro interaction of aniline (type II binding compound) only slightly affect the peroxidase activity. It is suggested that LAHPO and type I binding compounds are competing for the hydrophobic binding site on cytochrome p-450, while type II binding compounds such as aniline negate electron transfer non-competitively by combining with the heme.


Clinical application of 2.7M Cytogenetics array for CNV detection in subjects with idiopathic autism and/or intellectual disability.
Higher resolution whole-genome arrays facilitate the identification of smaller copy number variations (CNVs) and their integral genes contributing to autism and/or intellectual disability (ASD/ID). Our study describes the use of one of the highest resolution arrays, the Affymetrix(®) Cytogenetics 2.7M array, coupled with quantitative multiplex polymerase chain reaction (PCR) of short fluorescent fragments (QMPSF) for detection and validation of small CNVs. We studied 82 subjects with ASD and ID in total (30 in the validation and 52 in the application cohort) and detected putatively pathogenic CNVs in 6/52 cases from the application cohort. This included a 130-kb maternal duplication spanning exons 64-79 of the DMD gene which was found in a 3-year-old boy manifesting autism and mild neuromotor delays. Other pathogenic CNVs involved 4p14, 12q24.31, 14q32.31, 15q13.2-13.3, and 17p13.3. We established the optimal experimental conditions which, when applied to select small CNVs for QMPSF confirmation, reduced the false positive rate from 60% to 25%. Our work suggests that selection of small CNVs based on the function of integral genes, followed by review of array experimental parameters resulting in highest confirmation rate using multiplex PCR, may enhance the usefulness of higher resolution platforms for ASD and ID gene discovery.


The GABA agonist THIP a muscimol analogue, does not interfere with the benzodiazepine binding site on rats cortical membranes.
THIP, a cyclic analogue of muscimol, is a powerful GABA agonist. It is as active as GABA in displacing [3H]muscimol from its binding site to cerebellar membranes (IC50 = 31.5 +/- 2.5 mM). However, unlike muscimol or GABA, it is devoid of any modulatory interaction with the benzodiazepine binding site on rat's cortical membranes. Homotaurine, isoguvacine and imidazole acetic acid are less active than muscimol and GABA for increasing the affinity of [3H]diazepam to cortical membrane preparations.


[Pregnancy and delivery satisfaction of 424 patients in Perinatal Health Network « Sécurité Naissance » of Pays-de-la-Loire area].
One method of evaluating a perinatal policy measuring user satisfaction is an important issue. The objective of the study was to measure satisfaction with the monitoring of pregnancy, childbirth and maternity stay. Each volunteer maternity received a list of all births during one week in March-April 2008. The first mailing of questionnaires was conducted by post with stamped envelopes for the reply, after 2months in May and June 2008. A second reminder was made in July 2008. Responses to questions were coded using a Likert scale with four degrees with "very satisfied", "satisfied," "not very satisfied" and "not satisfied" with a quote by 4 to 1. The results are presented with the proportions of satisfied women, with radar diagrams. Transformation of responses with scores of 20 was established. In total, 424 responses were obtained in 22 maternities (/24), on 524 questionnaires sent (response rate 80.9 %). A comparison of mothers who responded to those who did not respond showed an over-representation of senior and middle managers and department. The average response time from birth was ten weeks±1 (8-26). The early prenatal care (known as the 4th month) was ignored (the word) by 58 % of women, but satisfying for those who have had while preparing for the birth, information on ultrasounds, tests on blood testing were satisfactory. A total of 13.2 % of women were hospitalized, and 94.9 % of cases, the information was obtained with 96.5 % satisfaction for the explanations. Mothers were met for the monitoring of pregnancy to 95.4 %. At delivery, the reception was well received with 94.7 % of satisfaction, like attention paid to patients with 93.5 % satisfied. The satisfaction score for delivery in general (with or without cesarean) was 16.5±4.0 (out of 20) with 92.5 % satisfied. The score for the cesarean section was 16.3 versus 16.6 for the low channels (not significant [NS]) in the case of anesthesia of 16.5 versus 16.7 (NS) in case of episiotomy of 15.9 versus 16.9 (P<0.05). The length of postpartum stay was found too short in case of 4.8 % (4.7 days), correct in 78.6 % (4.8 days), too long in 15.9 % (4.8 days). The satisfaction score for delivery in general (with or without cesarean) was 16.5 out of 20 with 92.5 % of satisfied. Also, 73.1 % of mothers tended to agree about the useful information for baby; 77.8 % thought that breastfeeding went well. The total score for pregnancy and childbirth is averaging 16.1, with 95.7 % of satisfied. The dissatisfying factors for 17 women have been linked in univariate to a department, the choice of maternity proximity and the existence of an episiotomy. Multivariate analysis was not significant criteria of discontent. Users respond to this type of investigation and seem satisfied with the care provided, in accordance with published data. The analysis of satisfaction and sources of dissatisfaction can improve treatments. The limits of the notion of satisfaction are analyzed.


Primary cervical spine carcinoid tumor in a woman with arm paresthesias and weakness: a case report.
Carcinoid tumors are neuroendocrine neoplasms derived from the enterochromaffin cells. Central nervous system involvement is rare and has been reported either as metastases to the brain and spine or primary tumors involving the sacrococcygeal spine. We report the first case of a primary carcinoid tumor of the cervical spine. A 50-year-old African-American woman presented with a 4-month history of numbness, paresthesias, and mild left-hand weakness. Magnetic resonance imaging of her cervical spine revealed a homogenously enhancing extradural mass, indenting the cervical cord and expanding the left neural foramen at C7-T1. A C7 corpectomy, en bloc resection of the tumor, and anterior C6-T1 fusion were performed to decompress the spinal cord and nerves and provide stability. Postoperative histopathologic examination and immunohistochemical analysis were consistent with carcinoid tumor. There has been no recurrence at the 6-year follow-up visit. Primary cervical carcinoid tumor is extremely rare, but should be included in the differential diagnosis of enhancing expansile extradural masses compressing the spinal cord and nerves. Surgical resection may provide a definitive cure.


Coronary Artery Bypass Surgery Without Saphenous Vein Grafting: JACC Review Topic of the Week.
Approximately 95% of patients of any age undergoing contemporary, coronary bypass surgery will receive at least 1 saphenous vein graft (SVG). It is recognized that SVG will develop progressive and accelerated atherosclerosis, resulting in a stenosis, and in occlusion that occurs in 50% by 10 years postoperatively. For arterial conduits, there is little evidence of progressive failure as for SVG. Could avoidance of SVG (total arterial revascularization [TAR]) lead to a different late (>5 year) survival? A literature review of 23 studies (N = 100,314 matched patients) at a mean 8.8 years postoperative found reduced all-cause mortality for TAR (HR: 0.77; 95% CI: 0.71-0.84; P < 0.001). An expanded analysis with a new unpublished data set (N = 63,288 matched patients) was combined with the literature review (N = 127,565). It found reduced all-cause mortality for TAR (HR: 0.78; 95% CI: 0.72-0.85; P < 0.001). Additional Bayesian analysis found a very high probability of a TAR-associated reduction all-cause mortality.


Anti-nociceptive effects induced by intrathecal injection of BmK AS, a polypeptide from the venom of Chinese-scorpion Buthus martensi Karsch, in rat formalin test.
Asian scorpion Buthus martensi Karsch (BmK) is widely used to treat neurological symptoms, especially chronic pain, in traditional Chinese medicine for thousands of years. BmK AS, a polypeptide from BmK venom, could produce peripheral potent anti-nociceptive effects in rats. In the present study, spinal anti-nociceptive effects of BmK AS were investigated in rat formalin test. Spinal anti-nociceptive activity of BmK AS was studied using formalin test in rats. BmK AS in doses of 0.02, 0.1 and 0.5 microg was administered intrathecally before formalin injection 10 min. The suppression by intrathecal injection of BmK AS on formalin-induced spontaneous nociceptive behaviors and spinal c-Fos expression were investigated. Intrathecal injection of BmK AS markedly reduced formalin-evoked biphasic spontaneous nociceptive behaviors in a dose-dependent manner. Formalin-induced c-Fos expression could be dose-dependently inhibited by BmK AS in superficial (I-II), the nucleus proprius (III and IV) and deep (V-VI) dorsal horn laminae, but not in the ventral gray laminae (VII-X) of lumbar spinal cord. The suppression by BmK AS on c-Fos expression in superficial laminaes was much stronger than that in deep laminaes. The present study demonstrates that BmK AS is capable of producing remarkable anti-nociceptive effects not only in periphery but also in spinal cord.


Three-dimensional anatomy of the cancellous structures within the proximal femur from computed tomography data.
Quantitative computed tomography was used to investigate the three-dimensional architecture and the density distribution of the cancellous structures of the proximal femur. We examined 10 femora from the cadavera of 10 individuals, 47-83 years old at the time of death. Three anatomic elements could be distinguished: the epiphysis, the epiphyseal scar, and the metaphysis. Although these elements constitute a functional unit, their individual cancellous patterns revealed significant structural differences. The epiphyseal segment had a more reticulate cancellous appearance, whereas the metaphysis demonstrated a more longitudinally oriented trabecular distribution. The three-dimensional reconstruction of the densest epiphyseal trabecular groups showed two different patterns: a dumbbell type (found in eight bones) and a hemispheric type (found in two bones). The epiphyseal scar was a clearly recognizable high-density structure found in all 10 bones. The epiphyseal scar-diaphysis angle was 13-26 degrees higher than the center column-diaphysis angle. The scar appeared as a tray supporting the epiphyseal cancellous structures, supported itself by the metaphyseal intersection of the main compressive and the arcuate trabecular systems. This intersection always occurred in a relatively small band-shaped zone under the central third of the epiphyseal scar. These three discrete anatomical segments within the proximal femur may reflect developmental and functional adaptations determined by joint incongruity or eccentric muscular activity. The present data will serve as a reference for future studies in which the cancellous patterns are used to help with the early diagnosis of states of disease.


Telomerase immortalization of neuronally restricted progenitor cells derived from the human fetal spinal cord.
Lineage-restricted progenitors of the central nervous system (CNS) are not readily expandable because their mitotic competence is limited. Here we used retroviral overexpression of human telomerase reverse transcriptase (hTERT) to immortalize progenitors from human fetal spinal cord. The hTERT-immortalized cells divided in basic fibroblast growth factor (bFGF) expressed high telomerase activity, and gave rise to phenotypically restricted subpopulations of either glia or neurons. The latter included a prototypic line, hSC11V-TERT, that gave rise only to neurons. These included both chx10(+) interneurons and Islet1(+)/Hb9(+)/ChAT(+) motor neurons; the latter were recognized by green fluorescent protein (GFP) driven by the Hb9 enhancer. The neurons were postmitotic and achieved electrophysiologic competence. Upon xenograft to both fetal rat brain and injured adult spinal cord, they matured as neurons and survived for 6 months, with no evident tumorigenesis. The cells have survived >168 doublings in vitro, with karyotypic normalcy and without replicative senescence. hTERT overexpression thus permits the generation of progenitor lines able to give rise to phenotypically restricted neurons.


Methyl-beta-cyclodextrin, a specific cholesterol-binding agent, inhibits melanogenesis in human melanocytes through activation of ERK.
Cholesterol has been suggested to regulate cell differentiation. In this study, we have examined the effects of cholesterol modulation on pigmentation of skin using a treatment with methyl-beta-cyclodextrin (MbetaCD), a specific cholesterol-binding agent. Treatment with MbetaCD reduced pigmentation in human melanocyte and cultured skin. This decrease in pigmentation was related to the inhibition of the expression of tyrosinase and microphthalmia-associated transcription factor of melanocytes. Stimulation of melanocytes with MbetaCD led to the time-dependent phosphorylation of extracellular signal-regulated kinase (ERK). Furthermore, ERK functionally regulated the MbetaCD-induced melanin formation in melanocytes; a ERK inhibitor, PD98059, almost completely attenuated the MbetaCD-mediated inhibition of melanin synthesis and down-regulation of MITF and tyrosinase expression. These results suggest that cholesterol reduction by MbetaCD inhibit melanin synthesis via ERK activation and subsequent MITF downregulation.


Mortality patterns, 1993-98, in a rural area of Burkina Faso, West Africa, based on the Nouna demographic surveillance system.
The Nouna demographic surveillance system database was analysed for the period 1993-98. Basic demographic parameters, age-specific and age-standardized mortality rates were calculated and a seasonal variation in mortality was analysed. Poisson regression was used to model the calculated mortality rates and to investigate the seasonal mortality pattern. Both the population distribution by age and the mortality rates reflect a typical pattern of population structures and total mortality in rural Africa as a whole: high childhood mortality and a young population (about 60% are up to age 25; about 10% above age 64). We identified a significant seasonal pattern with highest mortality rates in February. Demographic surveillance systems in Africa provide a viable method for the collection of reliable data on vital events in rural Africa and should therefore be established and supported.


Low phospholipids associated cholelithiasis syndrome in a young women: A rare case report.
Low phospholipid-associated cholelithiasis (LPAC) is a rare, still poorly understood genetic disorder characterized by the association of an ABCB4 mutation and low biliary phospholipid concentration with recurrent cholelithiasis, responsible for the development of intrahepatic lithiasis in adults. The mutation of the ABCB4 gene, which codes for the ABCB4/MDR3 ductal protein, a biliary transporter, leads to precipitation of cholesterol crystals in the bile ducts leading to the formation of intrahepatic stones. The diagnosis should be suspected when at least 2 of the following criteria are present: onset of symptoms before age 40; recurrence of biliary symptoms (biliary colic, jaundice, cholangitis, acute pancreatitis) after cholecystectomy; presence of echogenic foci in the liver indicative of intrahepatic stones or biliary sludge; previous episode(s) of intrahepatic cholestasis during pregnancy; and a family history of gallstones in first degree relatives. Imaging techniques, especially ultrasound, play an important role in the detection of intrahepatic stones. The majority of clinical situations are simple and not serious, often managed by medical treatment with ursodeoxycholic acid, but certain complicated forms may require more invasive endoscopic or surgical treatment. We report a case of a 43-year-old woman, cholecystectomized 5 years ago, who presented with liver colic-like pain with cytolysis and biological cholestasis. Ultrasound and MRI showed the presence of intrahepatic calculi disseminated along the bile duct pathway creating a comet tail appearance and generating a posterior shadow cone. The interrogation of the patient showed that her sister was being followed for LPAC syndrome. The diagnosis of LPAC syndrome was retained and the patient was put under medical treatment with ursodeoxycholic acid with regular clinical, biological and radiological follow-up.


Use of HLA marker associations and HLA haplotype linkage to estimate disease risks in families with gluten-sensitive enteropathy.
Based on a two-locus, double recessive model, we derive formulas for the risks that relatives of individuals with gluten-sensitive enteropathy (GSE) will also develop the disease. The calculations take advantage of: the linkage between the HLA locus and one of the two proposed GSE loci, and the preferential association of the HLA-DR3 and DR7 alleles with the GSE disease allele that occupies the HLA-linked locus. We use Bayes' rule to quantitate the strength of the association between the GSE disease allele and the HLA marker allele. This method predicts that siblings of the proband have an overall 10% risk for GSE, which is consistent with observed family data. This predicted risk rises to 30% when siblings are HLA-identical to the proband (also consistent with observed data) or when the sibling has the DR3 allele in the HLA haplotypes not shared with the proband. In those populations where DR7 also is associated with GSE, siblings of probands have a 10% predicted risk for GSE when only one HLA haplotype is shared with the proband and DR7 is included in the unshared haplotype. Other DR alleles are associated with much lower disease risks. By separating individuals into high and low risk groups, HLA typing identifies those individuals who would benefit from further diagnostic procedures. This general strategy should be applicable to other multilocus, marker-associated diseases.


Mechanism-of-action determination of GMP synthase inhibitors and target validation in Candida albicans and Aspergillus fumigatus.
Mechanism-of-action (MOA) studies of bioactive compounds are fundamental to drug discovery. However, in vitro studies alone may not recapitulate a compound's MOA in whole cells. Here, we apply a chemogenomics approach in Candida albicans to evaluate compounds affecting purine metabolism. They include the IMP dehydrogenase inhibitors mycophenolic acid and mizoribine and the previously reported GMP synthase inhibitors acivicin and 6-diazo-5-oxo-L-norleucine (DON). We report important aspects of their whole-cell activity, including their primary target, off-target activity, and drug metabolism. Further, we describe ECC1385, an inhibitor of GMP synthase, and provide biochemical and genetic evidence supporting its MOA to be distinct from acivicin or DON. Importantly, GMP synthase activity is conditionally essential in C. albicans and Aspergillus fumigatus and is required for virulence of both pathogens, thus constituting an unexpected antifungal target.


Prevention and Therapy of Preterm Birth. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/025, September 2022) - Part 1 with Recommendations on the Epidemiology, Etiology, Prediction, Primary and Secondary Prevention of Preterm Birth.
Aim This revised guideline was coordinated by the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (OEGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). It aims to improve the prediction, prevention, and management of preterm birth, based on evidence from the current literature, the experience of members of the guidelines commission, and the viewpoint of self-help organizations. Methods The members of the contributing professional societies and organizations developed recommendations and statements based on international literature. The recommendations and statements were presented and adopted using a formal process (structured consensus conferences with neutral moderation, written Delphi vote). Recommendations Part 1 of this short version of the guideline presents statements and recommendations on the epidemiology, etiology, prediction, and primary and secondary prevention of preterm birth.


Combined modality treatment for prostate cancer: role of chemotherapy.
Chemotherapy for prostate cancer currently has an established role in the treatment of hormone-refractory prostate cancer. There is strong evidence that combined modality treatment with androgen ablation in addition to radiotherapy provides a benefit above and beyond radiotherapy alone in patients with a poor prognosis, perhaps because of an effect of androgen ablation on subclinical distant disease. There are currently several clinical trials investigating whether the addition of chemotherapy with known efficacy in the hormone-refractory setting can provide a survival advantage when used adjuvantly. The role of chemotherapy for patients with nonmetastatic, hormone-naive prostate cancer will be discussed.


Neurobiological underpinnings of sensation seeking trait in heroin abusers.
Neurobiological investigation of heroin revealed that abusers of this highly addictive substance show dysregulation in brain circuits for reward processing and cognitive control. Psychologically, personality traits related to reward processing and cognitive control differed between heroin abusers and non-abusers. Yet, there is no direct evidence on the relationship between these neurobiological and psychological findings on heroin abusers, and whether such relationship is altered in these abusers. The present study filled this research gap by integrating findings obtained via magnetic resonance imaging (structural volume and resting-state functional connectivity) and self-reported personality trait measures (Zuckerman׳s Sensation Seeking Scale and Barratt Impulsivity Scale) on 33 abstinent heroin users and 30 matched healthy controls. The key finding is a negative relationship between high sensation seeking tendency and midbrain structural volume in the heroin users. Importantly, there was stronger coupling between the midbrain and ventromedial prefrontal cortex and weaker coupling between the midbrain and dorsolateral prefrontal cortex in heroin users. Our findings offer significant insight into the neural underpinning of sensation seeking in heroin users. Importantly, the data shed light on a novel relationship between the mesolimbic-prefrontal pathway of the reward system and the high sensation seeking personality trait in heroin abusers.


Leptin Receptor Gene Polymorphisms and the Risk of Non-Alcoholic Fatty Liver Disease and Coronary Atherosclerosis in the Chinese Han Population.
Leptin receptor (LEPR) polymorphisms have been reported to be associated with lipid metabolism and insulin resistance in various populations. However, whether LEPR polymorphisms are associated with the risks of non-alcoholic fatty liver disease (NAFLD) and coronary atherosclerosis in the Chinese Han population remains unknown. To investigate the association of LEPR polymorphisms at Q223R and K109R with the risks of NAFLD and coronary atherosclerosis in the Chinese Han population. Genotypes of LEPR Q223R and K109R were determined by polymerase chain reaction followed by sequencing in patients with NAFLD (n = 554), coronary atherosclerosis (n = 421), and healthy controls (n = 550). Serum lipid profiles were determined using biochemical methods. Pearson's χ(2) test was used to check for Hardy-Weinberg equilibrium and to analyze the distributions of genotypes' alleles between groups. Baseline characteristics were analyzed using student's t-test, paired-samples t-test, or the χ(2) test where appropriate. The LEPR Q223R A allele significantly reduced the risks of both NAFLD and coronary atherosclerosis (OR = 0.683, 95% CI: 0.527 - 0.884, P = 0.004 and OR = 0.724, 95% CI: 0.548 - 0.955, P = 0.022, respectively). Compared to controls, no significant differences in the genotype and allele frequencies of K109R were found in the NAFLD and coronary atherosclerosis populations, respectively. However, there was a significantly increased risk of coronary atherosclerosis in NAFLD patients who carried the K109R A allele (OR = 2.283, 95% CI: 1.556 - 3.348, P < 0.001). LEPR Q223R polymorphisms may confer a significant risk of NAFLD and coronary atherosclerosis. The A allele in the K109R polymorphism might be considered an independent risk factor for coronary atherosclerosis in NAFLD patients.


Coronary arterial anatomy in patients with left ventricular systolic dysfunction without chest pain or previous myocardial infarction.
Patients with left ventricular systolic dysfunction without chest pain or previous myocardial infarction are unlikely to have 3-vessel coronary artery disease and are very unlikely to have coronary anatomy suitable for bypass grafting. Of our 108 subjects, only 3 (3%) had 3-vessel coronary artery disease thought to be suitable for revascularization.


INFLUENCE OF INJURY ON DYNAMIC POSTURAL CONTROL IN RUNNERS.
Injury has been linked with altered postural control in active populations. The association between running injury and dynamic postural control has not been examined. The purpose of this study was to examine dynamic postural control in injured and uninjured runners using the Star Excursion Balance Test (SEBT), Time to Stabilization (TTS) of ground reaction forces following a single-leg landing, and postural stability indices reflecting the fluctuations in GRFs during single-leg landing and stabilization tasks (forward and lateral hop). It was hypothesized that dynamic postural control differences would exist between runners with a history of injury that interrupted training for ≥7 days (INJ) when compared to runners without injury (CON). Case-control study. Twenty-two INJ (14 F, 8 M; 23.7 ± 2.1 y; 22.3 ± 2.8 kg/m2; 29.5 ± 16.3 mi/wk) currently running > 50% pre-injury mileage without pain were compared with twenty-two matched CON (14F, 8M; 22.7 ± 1.2 y; 22.7 ± 2.7 kg/m2; 31.2 ± 19.6 mi/wk). INJ group was stratified by site of injury into two groups (Hip/Thigh/Knee and Lower Leg/Ankle/Foot) for secondary analysis. Leg length-normalized anterior, posterolateral, and posteromedial reach distances on the SEBT, medial/lateral and anterior/posterior ground reaction force TTS, directional postural stability indices, and a composite dynamic postural stability index (DPSI), were assessed using mixed model ANOVA (α=0.05) and effect sizes (d). No group X direction interaction or group differences were observed for the SEBT (p=0.51, 0.71) or TTS (p=0.83, 0.72) measures. A group X direction interaction was found for postural stability indices during the forward landing task (p<0.01). Both Hip/Thigh/Knee and Lower leg/Ankle/Foot INJ groups demonstrated a greater vertical postural stability index (VPSI) (p=0.01 for both, d=0.80, 0.95) and DPSI (p=0.01, 0.02, d=0.75, 0.93) when compared to CON suggesting impaired balance control. A group X direction interaction was also found for postural stability indices during the lateral landing task (p=0.03). Only the Hip/Thigh/Knee INJ runners displayed a greater VPSI (p=0.01, d=0.91) and DPSI (p=0.017, d=0.89) when compared to CON. When compared to CON, INJ runners demonstrated impaired dynamic control of vertical forces when performing the single leg landing and stabilization tasks. Clinicians should consider addressing dynamic control of vertical loads through functional tasks during the rehabilitation of running injury. Level 3.


Recombinant activated protein C attenuates endothelial injury and inhibits procoagulant microparticles release in baboon heatstroke.
We tested the hypothesis that the antithrombotic and cytoprotective effects of recombinant human activated protein C (rhAPC) protect baboons against the lethal effects of heatstroke. Fourteen anesthetized baboons assigned randomly to rhAPC (n=7) or control group (n=7) were heat-stressed in a prewarmed incubator at 44 to 47 degrees C until systolic blood pressure fell below 90 mm Hg, which signaled severe heatstroke. rhAPC was administered intravenously (24 microg/kg/h) for 12 hours at onset of heatstroke. Heat stress induced coagulation and fibrinolysis activation as evidenced by a significant increase from baseline levels in plasma levels of thrombin-antithrombin (TAT) complexes, tissue plasminogen activator, and D-dimer. Heat stress elicited cell activation/injury as assessed by the release of interleukin (IL)-6, soluble thrombomodulin, and procoagulant microparticles (MPs). rhAPC did not significantly reduce heatstroke-induced thrombin generation, and D-dimer and had no effect on fibrinolytic activity. In contrast, rhAPC infusion attenuated significantly the plasma rise of IL-6 and inhibited the release of soluble thrombomodulin and MPs as compared with control group. No difference in survival was observed between rhAPC-treated and control group. rhAPC given to heatstroke baboons provided cytoprotection, but had no effect on heatstroke-induced coagulation activation and fibrin formation. Inhibition of MPs by rhAPC suggested a novel mechanism of action for this protein.


Circularity and self-cleavage as a strategy for the emergence of a chromosome in the RNA-based protocell.
It is now popularly accepted that an "RNA world" existed in early evolution. During division of RNA-based protocells, random distribution of individual genes (simultaneously as ribozymes) between offspring might have resulted in gene loss, especially when the number of gene types increased. Therefore, the emergence of a chromosome carrying linked genes was critical for the prosperity of the RNA world. However, there were quite a few immediate difficulties for this event to occur. For example, a chromosome would be much longer than individual genes, and thus more likely to degrade and less likely to replicate completely; the copying of the chromosome might start at middle sites and be only partial; and, without a complex transcription mechanism, the synthesis of distinct ribozymes would become problematic. Inspired by features of viroids, which have been suggested as "living fossils" of the RNA world, we supposed that these difficulties could have been overcome if the chromosome adopted a circular form and small, self-cleaving ribozymes (e.g. the hammer head ribozymes) resided at the sites between genes. Computer simulation using a Monte-Carlo method was conducted to investigate this hypothesis. The simulation shows that an RNA chromosome can spread (increase in quantity and be sustained) in the system if it is a circular one and its linear "transcripts" are readily broken at the sites between genes; the chromosome works as genetic material and ribozymes "coded" by it serve as functional molecules; and both circularity and self-cleavage are important for the spread of the chromosome. In the RNA world, circularity and self-cleavage may have been adopted as a strategy to overcome the immediate difficulties for the emergence of a chromosome (with linked genes). The strategy suggested here is very simple and likely to have been used in this early stage of evolution. By demonstrating the possibility of the emergence of an RNA chromosome, this study opens on the prospect of a prosperous RNA world, populated by RNA-based protocells with a number of genes, showing complicated functions.


Fast biodegradation of long-alkanes by enhancing bacteria performance rate by per-oxidation.
The long-alkanes biodegradation rate was generally found slow during widely used pre-oxidation combined with biodegradation for oil contamination treatment, resulting in long and unsustainable removal. In this study, different chitosan content was used to produce iron catalysts for pre-oxidation, and nutrients were added for the long-alkanes biodegradation experiment. Mechanism of Fenton pre-oxidation and improvement in the biodegradation rate of long-alkanes were studied by analyzing the change in organic matter and bacterial community structure, the amount and activity of bacteria in the biological stage, and the degradation amount long-alkanes hydrocarbon before and after pre-oxidation. Results showed that the destruction of bacteria greatly reduced when hydroxyl radical intensity decreased to 4.40 a.u.. Also, the proportion of humic acid-like was high (40.88%), and the community structure was slightly changed with the pre-oxidation for the fast biodegradation (FB) group. In the subsequent biodegradation, it was found that the degradation rate of each long-alkanes in the FB group increased significantly (C30: 4.18-8.32 mg/(kg·d)) with the increase of the degradation of long-alkanes (10-50%). Further studies showed that the high nutrient dynamics (6.05 mg/(kg·d)) of the FB group resulted in high bacteria performance rate (0.53 mol CO2 × log CFU/(104 g2 d)), which further accelerated the substrate transformation(41%). Therefore, the biodegradation rate of long-alkanes was increased (43.8 mg/(kg·d)) with the removal rate of long-alkanes of 76%. The half-life of long-alkanes for the FB group (64 d) was 33 d shorter than the slow biodegradation group (99 d). These results exhibited that pre-oxidation regulation can shorten the bioremediation cycle by improving the biodegradation rate of long-alkanes. This research has good engineering application value.


Refining homology models by combining replica-exchange molecular dynamics and statistical potentials.
A protocol is presented for the global refinement of homology models of proteins. It combines the advantages of temperature-based replica-exchange molecular dynamics (REMD) for conformational sampling and the use of statistical potentials for model selection. The protocol was tested using 21 models. Of these 14 were models of 10 small proteins for which high-resolution crystal structures were available, the remainder were targets of the recent CASPR exercise. It was found that REMD in combination with currently available force fields could sample near-native conformational states starting from high-quality homology models. Conformations in which the backbone RMSD of secondary structure elements (SSE-RMSD) was lower than the starting value by 0.5-1.0 A were found for 15 out of the 21 cases (average 0.82 A). Furthermore, when a simple scoring function consisting of two statistical potentials was used to rank the structures, one or more structures with SSE-RMSD of at least 0.2 A lower than the starting value was found among the five best ranked structures in 11 out of the 21 cases. The average improvement in SSE-RMSD for the best models was 0.42 A. However, none of the scoring functions tested identified the structures with the lowest SSE-RMSD as the best models although all identified the native conformation as the one with lowest energy. This suggests that while the proposed protocol proved effective for the refinement of high-quality models of small proteins scoring functions remain one of the major limiting factors in structure refinement. This and other aspects by which the methodology could be further improved are discussed.


Benzopyrans from Curvularia sp., an endophytic fungus associated with Ocotea corymbosa (Lauraceae).
An isolate of Curvularia sp. was obtained from the leaves of Ocotea corymbosa, a native plant of the Brazilian Cerrado. The ethyl acetate extract from culture of this fungus afforded two benzopyran derivatives: (2'S)-2-(propan-2'-ol)-5-hydroxy-benzopyran-4-one (2) and 2,3-dihydro-2-methyl-benzopyran-4,5-diol (4); and two known benzopyrans: 2-methyl-5-methoxy-benzopyran-4-one (1) and (2R)-2,3-dihydro-2-methyl-5-methoxy-benzopyran-4-one (3). The structures of 2 and 4 were established on the basis of comprehensive spectroscopic analysis, mainly using 1D and 2D NMR experiments. The benzopyrans 1 and 2 showed weak in vitro antifungal activity against Cladosporium sphaerospermum and C. cladosporioides. Analyses of the biological activities were also carried out on HeLa (human cervix tumor) and CHO (Chinese hamster ovary) cells, aiming to evaluate their potential effects on mammalian cell line proliferation. Results from both cell lines indicated that compound 2 was able to induce cell proliferation: 70% on HeLa cells and 25% on CHO cells.


Personal and neighborhood socioeconomic status and indices of neighborhood walk-ability predict body mass index in New York City.
Past research has observed inverse associations between neighborhood and personal level measures of socioeconomic status and body mass index (BMI), but has not assessed how personal and neighborhood-level measures might interact together to predict BMI. Using a sample of 13,102 adult residents of New York City who participated in a health survey, cross-sectional multi-level analyses assessed whether personal income, education and Zip code-level poverty rates were associated with BMI. Demographic, income, education and objectively measured height and weight data were collected in the survey and poverty rates and the proportion of Black and Hispanic residents in the subject's Zip code were retrieved from the 2000 Census. Zip code-level population density and land use mix, indices of neighborhood walk-ability which are often higher in lower income neighborhoods and are associated with lower BMI, were also measured. After controlling for individual and Zip code-level demographic characteristics, increasing income was associated with lower BMI in women but not in men, and college and graduate level education was associated with lower BMI in both men and women. After control for income and individual and Zip code-level demographic characteristics, higher Zip code poverty rate was unassociated with BMI. However, as expected, indices of neighborhood walk-ability acted as substantial inverse confounders in the relationship between Zip code poverty rate and BMI. After further adjustment for indices of neighborhood walk-ability, Zip code poverty rate became significantly, and positively associated with BMI in women. Among women, the inverse association between income and BMI was significantly stronger in richer compared to poorer Zip codes. In men and women, the association between college and graduate education and lower BMI was significantly stronger in richer versus poorer Zip codes. These analyses suggest that neighborhood socioeconomic context influences how personal socioeconomic status interact in predicting boby size.


Is the Kok effect a respiratory phenomenon? Metabolic insight using 13 C labeling in Helianthus annuus leaves.
The Kok effect is a well-known phenomenon in which the quantum yield of photosynthesis changes abruptly at low light. This effect has often been interpreted as a shift in leaf respiratory metabolism and thus used widely to measure day respiration. However, there is still no formal evidence that the Kok effect has a respiratory origin. Here, both gas exchange and isotopic labeling were carried out on sunflower leaves, using glucose that was 13 C-enriched at specific C-atom positions. Position-specific decarboxylation measurements and NMR analysis of metabolites were used to trace the fate of C-atoms in metabolism. Decarboxylation rates were significant at low light (including above the Kok break point) and increased with decreasing irradiance below 100 µmol photons m-2 s-1 . The variation in several metabolite pools such as malate, fumarate or citrate, and flux calculations suggest the involvement of several decarboxylating pathways in the Kok effect, including the malic enzyme. Our results show that day respiratory CO2 evolution plays an important role in the Kok effect. However, the increase in the apparent quantum yield of photosynthesis below the Kok break point is also probably related to malate metabolism, which participates in maintaining photosynthetic linear electron flow.


Selective recruitment of stem cell donors with rare human leukocyte antigen phenotypes.
Many patients in need of a hematopoietic stem cell transplant do not find a fully matching donor although more than 11,000,000 potential donors are registered worldwide. Therefore, it is relevant to recruit donors who add diversity to the donor pool. We present the 'Roots' approach that includes the selection of already registered donors with rare HLA phenotypes and the recruitment of relatives of these donors. Two projects (Roots A and B) with different donor selection criteria were carried out. HLA phenotype frequency distributions of new donors differ significantly from the respective control groups: 2.7% of Roots A donors versus 1.1% of the control group have an HLA-AB phenotype that is unique in the DKMS file (P=0.001). Additionally, 39.5% of Roots B donors but only 18.3% of the control group have a unique HLA-ABDR phenotype (P<0.001). Similar results are found when phenotypes that are at most available 10 times in the DKMS donor file are analyzed. The results show that the Roots approach is generally suited to increasing the ratio of donors with rare HLA phenotypes in a donor file. Additional costs of Roots donor recruitment seem justified through the ratio of recruited donors with rare HLA phenotypes.


Nurses' strategies when providing for patients' aesthetic needs. Personal experiences of aesthetic means of expression.
The present study was conducted at five hospitals in Sweden. Data were collected by a random procedure from registered nurses (N = 165) in face-to-face interviews. The study reports on how and why nurses provide for patients' aesthetic needs. Open substantive coding of each interview fractured the data. The category of good for the patient was identified in the following nurses" statements: "The patient became relaxed" and "It distracted the patient from her pain." Regarding the question about how nurses provide for the patients' aesthetic needs, they did it in a nonactive manner. They used the basic service available at the wards. It could be concluded that although nurses show concern for patients' aesthetic needs, there is still more to be learned in this area of research. Nurses need to be encouraged to actively incorporate aesthetic means of expression in nursing practice.


Study protocol: A cluster randomised controlled trial of implementation intentions to reduce smoking initiation in adolescents.
The current literature suggests that forming implementation intentions (simple 'if-then' plans) about how to refuse the offer of a cigarette may be an effective intervention to reduce smoking initiation in adolescents. This study is a pragmatic trial to test the effectiveness and cost-effectiveness of such an intervention in reducing smoking initiation in a sample of UK adolescents. A cluster randomised controlled trial with at least 36 schools randomised to receive an implementation intention intervention targeting reducing smoking initiation (intervention group) or increasing homework (control group). Interventions will be conducted at the classroom level and be repeated every six months for four years (eight interventions). Objectively assessed (carbon monoxide monitor) and self-reported smoking plus smoking related cognitions (e.g., smoking intentions, attitudes, norms and self-efficacy) will be assessed at baseline and 12, 24, 36 and 48 months post baseline. Objectively assessed smoking at 48 months post baseline will be the primary outcome variable. Health economic analyses will assess life years gained. The results of the trial will provide information on the impact of a repeated implementation intention for refusing offers of cigarettes on rates of smoking initiation in adolescents. ISRCTN27596806.


Novel MEKC method for determination of sodium 2-mercaptoethanesulfonate in human plasma with in-capillary derivatization and UV detection.
Sensitive electrophoretic method for determination of total sodium 2-mercaptoethanesulfonate (mesna) in human plasma, based on the stacking with high salt concentration in MEKC and in-capillary derivatization with 2-chloro-1-methyllepidinium tetrafluoroborate followed by UV detection was developed. In the method 0.03molL(-1)pH 7 phosphate buffer with the addition of 0.01molL(-1) SDS, and 10% ACN was used as a BGE. The limit of quantification (LOQ) of the method was 0.5μmolL(-1). Linearity in detector response was observed over the range of 0.5-10μmolL(-1) with the correlation coefficient 0.9971. The intra- and inter-day accuracy (three concentration levels, 5 days, n=3) of the method ranged from 97.2 to 110.0% and from 94.0 to 101.2%, respectively. The novel MEKC method with UV detection proved to be suitable for determination of total mesna in human plasma.


Mu-Opioid (MOP) receptor mediated G-protein signaling is impaired in specific brain regions in a rat model of schizophrenia.
Schizophrenia is a complex mental health disorder. Clinical reports suggest that many patients with schizophrenia are less sensitive to pain than other individuals. Animal models do not interpret schizophrenia completely, but they can model a number of symptoms of the disease, including decreased pain sensitivities and increased pain thresholds of various modalities. Opioid receptors and endogenous opioid peptides have a substantial role in analgesia. In this biochemical study we investigated changes in the signaling properties of the mu-opioid (MOP) receptor in different brain regions, which are involved in the pain transmission, i.e., thalamus, olfactory bulb, prefrontal cortex and hippocampus. Our goal was to compare the transmembrane signaling mediated by MOP receptors in control rats and in a recently developed rat model of schizophrenia. Regulatory G-protein activation via MOP receptors were measured in [(35)S]GTPγS binding assays in the presence of a highly selective MOP receptor peptide agonist, DAMGO. It was found that the MOP receptor mediated activation of G-proteins was substantially lower in membranes prepared from the 'schizophrenic' model rats than in control animals. The potency of DAMGO to activate MOP receptor was also decreased in all brain regions studied. Taken together in our rat model of schizophrenia, MOP receptor mediated G-proteins have a reduced stimulatory activity compared to membrane preparations taken from control animals. The observed distinct changes of opioid receptor functions in different areas of the brain do not explain the augmented nociceptive threshold described in these animals.


Effects of vitamin D3, 17beta-estradiol, vasoactive intestinal peptide, and glutamate on electric coupling between rat osteoblast-like cells in vitro.
Osteoblast-like cells express receptors for various hormones and neurotransmitters that induce widespread actions in the bone to which intercellular communication and its modulation may contribute. Therefore, we examined the effects of the osteotropic hormones vitamin D3 (vitD3) and 17beta-estradiol (17beta-E2) as well as the neurotransmitter vasoactive intestinal peptide (VIP) and the excitatory amino acid glutamate (Glu) on gap junctions between rat osteoblast-like (ROB) cells in vitro. Electric coupling was measured by simultaneous intracellular recordings from neighboring cells. The coupling factor (cf) was calculated from membrane potential changes induced by alternate current injections into both cells. In ROB cells cf was increased by 5 x 10(-8) mol/L vitD3 to 130 +/- 13% (mean +/- SD; n = 6) of the initial value within 5-20 min. This effect was not reversible after washing with control saline for 10-15 min. In six cell pairs, cf was not affected by vitD3 (94 +/- 5%). In three cell pairs superfusion of 10(-8) mol/L E2 reduced cf to 80 +/- 6% within 10 min, whereas, in two cell pairs, this hormone improved cf to 140% within 20 min. Exposure of VIP (3 x 10(-8) mol/L) did not alter cf in the majority of cells (99 +/- 3%; n = 11). In five cell pairs, cf was improved within 5-15 min to 133 +/- 12%, whereas, in one cell pair, cf was reduced to 22% by VIP. In contrast, brief application of Glu (5 x 10(-3) mol/L) decreased cf to 75 +/- 5% (n = 5), whereas, in nine other cell pairs, cf was not affected (96 +/- 5%). The findings indicate that cell-cell coupling of gap junctions between bone cells can be altered by actions of hormones and transmitters in a cell-pair-specific way, which may depend on their functional state.


Organoiodine(III) Reagents as Active Participants and Ligands in Transition Metal-Catalyzed Reactions: Iodosylarenes and (Imino)iodoarenes.
This chapter overviews the roles of transition metal complexes having the organoiodine(III) reagents iodosylarenes (ArIO) and (imino)iodoarenes (ArINR) as ligands in catalysis. Mechanistic implications are discussed.


Theophylline-induced nociceptive behavioral response in mice: possible indirect interaction with spinal N-methyl-D-aspartate receptors.
Intrathecal administration of an adenosine receptor antagonist, theophylline, elicited nociceptive behavior such as licking, biting and scratching in mice. This behavioral response was dose-dependently reduced by simultaneous injection of an adenosine receptor agonist, 5'-N6-ethylcarboxamidoadenosine, or a selective N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonovalerate. This theophylline-induced behavior was not significantly reduced by the substance P (SP) analogue, the neurokinin receptor antagonist, [D-Arg1, D-Trp7.9, Leu11]SP (spantide). These results suggest the possibility that theophylline-induced nociceptive behavior may be mediated through interactions with both spinal adenosine- and NMDA receptors separately, or only through interaction(s) with adenosine receptors localized on the axon terminals of excitatory amino acid neurons. Present data have failed to reveal involvement of SP.


Peak exercise oxygen pulse and prognosis in chronic heart failure.
Cardiopulmonary variables, particularly peak oxygen consumption (peak VO(2)) corrected for total and lean body weight, have been confirmed to predict prognosis in patients with chronic systolic heart failure (HF). Only limited data are available on the prognostic ability of maximal oxygen (O(2)) pulse, an indicator of stroke volume and arteriovenous O(2) difference, especially when corrected for lean body mass. Cardiopulmonary exercise tests were performed in 209 consecutive patients with mild-to-moderate HF (mean ejection fraction 23%), followed for 19 +/- 12 months to determine the impact of maximal O(2) pulse in relation to other cardiopulmonary variables on major clinical events (13 cardiovascular deaths and 15 urgent transplantations). Compared with patients with clinical events, those without major events had a higher peak O(2) pulse (11.4 +/- 4.1 vs 9.2 +/- 2.3 ml/beat, p <0.0001) and body fat-adjusted peak O(2) pulse (15.6 +/- 5.6 vs 11.9 +/- 3.4 ml/beat, p <0.0001). In multivariate analysis, a low peak O(2) pulse was the strongest independent predictor of clinical events (chi-square 10.5, p <0.01). Although peak O(2) pulse was a stronger predictor for clinical events than any other exercise cardiopulmonary variable, including peak VO(2), peak VO(2) lean (defined as the VO(2) corrected for lean body mass), and percentage of predicted peak VO(2), this relation was further strengthened by correcting peak O(2) pulse for percent body fat (chi-square 12.4, p <0.001). In most subgroups (including women, obese subjects, those receiving beta blockers, and those with class III HF), peak O(2) pulse lean was similar to or superior to peak VO(2) lean for predicting major clinical events. Especially in patients who were class III HF and who were receiving beta blockers, peak VO(2) (cutoff 14 ml/kg/min) poorly predicted prognosis; risk stratification was best with peak O(2) pulse lean (cutoff 14 ml/beat). These data indicate the potential usefulness of peak O(2) pulse and lean body mass-adjusted O(2) pulse for predicting prognosis in patients with systolic HF.


White blood cell response to uphill walking and downhill jogging at similar metabolic loads.
The object of this study was to determine whether leukocytosis would occur in response to eccentric exercise, to concentric exercise, and/or to possible increases in serum cortisol levels. Eight men performed 2 bouts of exercise at 46% VO2max for 40 min. Subjects initially walked up a 10% grade (UW); 2 weeks later they jogged down a 10% grade (DJ), a form of eccentric exercise known to induce delayed onset muscle soreness (DOMS). Venous blood samples were drawn before and after each exercise bout (0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 5 h). Total and differential WBCc and serum cortisol levels were assessed. Results were analyzed using repeated measures ANOVA (2 x 11). Subjects experienced severe DOMS after DJ. There was a significant difference in TWBCc (p less than 0.0001) between UW and DJ. Post-hoc testing revealed no significant increase over baseline values for UW; after DJ there was a 46% increase over baseline values (p less than 0.05) initially seen at 1.0 h. These increases in TWBCc were predominantly a reflection of increases in neutrophils which were significant (p less than 0.0001) when compared to baseline values at 1.0, 1.5 and 2.0 h (approximately 60%). No significant neutrophil increases were seen after UW. Cortisol levels were similar for both groups pre-exercise (UW = 367.1 +/- 38.6, DJ = 320.2 +/- 44.16 nmol.L-1 means +/- SE) and decreased similarly for both groups after exercise, and thus were not related to the post-exercise neutrophilia.(ABSTRACT TRUNCATED AT 250 WORDS)


IRF3 contributes to sepsis pathogenesis in the mouse cecal ligation and puncture model.
Much remains to be learned regarding which components of the innate immune response are protective versus detrimental during sepsis. Prior reports demonstrated that TLR9 and MyD88 play key roles in the CLP mouse model of sepsis; however, the role of additional PRRs and their signaling intermediates remains to be explored. In a prior report, we demonstrated that the signal adaptor IRF3 contributes to the systemic inflammatory response to liposome:DNA. We hypothesized that IRF3 might likewise promote sepsis in the CLP model. Here, we present results demonstrating that IRF3-KO mice have reduced disease score, mortality, hypothermia, and bacterial load following CLP versus WT counterparts. This is paired with reduced levels of systemic inflammatory mediators in IRF3-KO mice that undergo CLP. We demonstrate that peritoneal cells from WT CLP mice produce more cytokines than IRF3-KO counterparts on a per-cell basis; however, there are more cells in the peritoneum of IRF3-KO CLP mice. Finally, we show that IRF3 is activated in macrophages cultured with live or sonicated commensal bacteria. These results demonstrate that IRF3 plays a detrimental role in this mouse model of sepsis.


CD28 superagonists: mode of action and therapeutic potential.
Some CD28-specific monoclonal antibodies (mAbs) have the surprising property to activate T-cells without the need for TCR ligation. This review summarizes the differences between these "superagonistic" and conventional CD28-specific mAbs with regard to binding specificity and signalling properties. Furthermore, the dramatic effects of in vivo application of CD28 superagonists with regard to the induction of regulatory T-cells and polyclonal T-cell expansion in lymphopenic settings are discussed under the aspect of potential therapeutic applications.


Comparative analysis of fibrinolytic properties of Alteplase, Tenecteplase and Urokinase in an in vitro clot model of intracerebral haemorrhage.
Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as an alternative therapy for spontaneous intracerebral and intraventricular haemorrhage (ICH and IVH). However, the MISTIE III and CLEAR III trial failed to show significant improvement of favourable outcomes. Besides experimental and clinical trials revealed neurotoxic effects of rtPA. The demand for optimization of fibrinolytic therapy persists. Herein, we used our recently devised clot model of ICH to systematically analyse fibrinolytic properties of rtPA, tenecteplase and urokinase. In vitro clots of human blood (size: 25 ml and 50 ml; age: 1.5 tenecteplase, 24 tenecteplase and 48 tenecteplase) were produced and equipped with a catheter into the clot core for drug delivery and drainage. Various doses of tenecteplase and urokinase with different treatment periods were examined (overall 117 clots), assessing the optimal dose and treatment time of these fibrinolytics. Clots were weighed before and at the end of treatment. These results were compared with clots treated with 1 mg rtPA or with 0.9% sodium chloride solution. The optimal treatment scheme of tenecteplase was found to be 100 IU with an incubation time of 30 min, for urokinase it was 50 000 IU with an incubation time of 20 min. The relative clot end weight of tenecteplase and urokinase (31.3±11.9%, 34.8 ±7.7%) was comparable to rtPA (36.7±10.7%). Larger clots were more effectively treated with tenecteplase compared to the control group (P=0.0013). urokinase and tenecteplase had similar lysis rates in aged clots and 90 min clots. One and two repetitive treatments with tenecteplase were as effective as two and three cycles of urokinase. In our in vitro clot model we could determine optimal treatment regimens of tenecteplase (100 IU, 30 min) and urokinase (50 000 IU, 20 min). Urokinase and tenecteplase were comparable in their fibrinolytic potential compared to 1mg rtPA in small clots and showed an effective lysis in aged clots. tenecteplase was more effective in larger clots.


Prevalence of preoperative cognitive impairment among elderly thoracic surgery patients and association with postoperative delirium: a prospective observational study.
Preoperative cognitive impairment (PCI) may increase the incidence of postoperative delirium (POD), yet screening for cognitive impairment is rarely performed. This study hypothesized that Mini-Cog for preoperative cognitive impairment screening predicts postoperative delirium. The prospective observational study recruited 153 elderly patients presenting for elective thoracic surgery. Cognitive function of these patients was screened using Mini-Cog preoperatively. We considered that patients with Mini-Cog scores ≤ 3 had cognitive impairment. Delirium was assessed using the Short CAM scale on postoperative days 1-5. Of the 153 participants, 54 (35.3%) were assigned to the PCI group, and 99 (64.7%) were assigned to the Normal group. Place of residence, education level, and history of hypertension were significantly different between the two groups (P < 0.05). 51 (33.3%) patients developed POD. Multifactorial analysis revealed that PCI (OR = 2.37, P = 0.028), older age (OR = 1.13, P = 0.009), ASA grade III (OR = 2.75, P = 0.012), and longer duration of anesthesia (OR = 1.01, P = 0.007) were associated with POD. Preoperative cognitive impairment is strongly associated with POD. Mini-Cog could be recommended for screening PCI. ClinicalTrials.gov, identifier NCT05798767.


Comparisons of the influenza virus A M2 channel binding affinities, anti-influenza virus potencies and NMDA antagonistic activities of 2-alkyl-2-aminoadamantanes and analogues.
The new 2-alkyl-2-aminoadamantanes and analogues 4-10 were designed and synthesized by simplification of the structure of the potent anti-influenza virus A spiranic aminoadamantane heterocycles 2 and 3. The aim of the present work was to examine the effects of bulky and extended lipophilic moieties attached to amantadine 1 on binding to the M2 channel and the resulting antiviral potency. The binding affinities of the compounds to the M2 protein of influenza virus A/chicken/Germany/27 (Weybridge strain; H7N7) were measured for the first time using an assay based on quenching of Trp-41 fluorescence by His-37 protonation, and their antiviral potencies were evaluated against the replication of influenza virus A H2N2 and H3N2 subtypes and influenza virus B in MDCK cells. Of the various 2-alkyl-2-aminoadamantanes, and analogues, spiro[piperidine-2,2'-adamantane] 3 had the strongest M2 binding and antiviral potency, which were similar those of amantadine 1. The relative binding affinities suggested that the rigid carbon framework provided by the pyrrolidine or piperidine rings results in a more favorable orientation inside the M2 channel pore as compared to large, freely rotating alkyl groups. The aminoadamantane derivatives exhibited similar NMDA antagonistic activity to amantadine 1. A striking finding was the antiviral activity of the adamantanols 4, and 6, which lack any NMDA antagonist activity.


[Partial reimbursement of prescription charges for generic drugs reduces costs for both health insurance and patients].
Rising costs of pharmaceuticals are a challenge to the public health care system. In collaboration with a company health insurance with 3143 members we analysed the economic benefit of reduced prescription fees for generic drugs in a 12-month period. Within the observation period 1 euro per prescription of a generic drug was reimbursed to the insurants. On the basis of 5 drug classes the prescribed proportion of generic drugs and the change in prescription pattern was computed. The acceptance of the intervention by the insurants was assessed using anonymous questionnaires. 42,219 drug prescriptons for insurants of the health insurance company were registered, with an overall cost of euro 843,954.95. In the observation period there was a 45% increase of the proportion of overall costs spent for generic drugs, from euro 78,325.65 to euro 110,419.90, together with a 38% increase of prescriptions of generic drugs. The expenditures for reimbursements of prescription payments amounted to euro 9,984 (euro 1-74 to insurants). In the 5 selected drug classes the proportion of generic drugs increased from 23% before the observation period to 40%, whereby a cost reduction of euro 2.47 per prescription was achieved. Taking into account an overall increase of prescriptions of the selected drugs, a cost reduction from euro 188,811.45 to euro 173,677.15 was accomplished. This intervention was considered useful by 84% of all insurants. Financial incentives for insurants by partial reimbursement of prescription charges are effective for increasing the proportion of generic substitutes and for controlling drug costs.


Infection induced SARS-CoV-2 seroprevalence and heterogeneity of antibody responses in a general population cohort study in Catalonia Spain.
Sparse data exist on the complex natural immunity to SARS-CoV-2 at the population level. We applied a well-validated multiplex serology test in 5000 participants of a general population study in Catalonia in blood samples collected from end June to mid November 2020. Based on responses to fifteen isotype-antigen combinations, we detected a seroprevalence of 18.1% in adults (n = 4740), and modeled extrapolation to the general population of Catalonia indicated a 15.3% seroprevalence. Antibodies persisted up to 9 months after infection. Immune profiling of infected individuals revealed that with increasing severity of infection (asymptomatic, 1-3 symptoms, ≥ 4 symptoms, admitted to hospital/ICU), seroresponses were more robust and rich with a shift towards IgG over IgA and anti-spike over anti-nucleocapsid responses. Among seropositive participants, lower antibody levels were observed for those ≥ 60 years vs < 60 years old and smokers vs non-smokers. Overweight/obese participants vs normal weight had higher antibody levels. Adolescents (13-15 years old) (n = 260) showed a seroprevalence of 11.5%, were less likely to be tested seropositive compared to their parents and had dominant anti-spike rather than anti-nucleocapsid IgG responses. Our study provides an unbiased estimate of SARS-CoV-2 seroprevalence in Catalonia and new evidence on the durability and heterogeneity of post-infection immunity.


Dominantly inherited congenital cerebellar ataxia with atrophy of the vermis.
We report a mother and daughter with congenital cerebellar ataxia and normal intelligence. Computed tomography revealed localized atrophy of the cerebellar vermis. This is the second case report of dominantly inherited, nonprogressive, congenital cerebellar ataxia.


Effect of PPADS on achondroplasic chondrocytes: inhibition of FGF receptor type 3 over-activity.
Achondroplasia, results from a mutation in the FGF receptor type 3, leading to receptor hyperactivation and subsequent amplification of FGF receptor type 3 signals. We have tested the ability of pyridoxal-5'-phosphate-6-azophenyl-2', 4'-disulfonate (PPADS) to decrease the overactivation and signalling of FGF receptor type 3 in achondroplasic chondrocytes. PPADS reduced the tyrosine phosphorylation of FGF receptor type 3 triggered by fibroblast growth factor 9 (FGF9) (50% reduction), as well as the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway. As a consequence of this inhibitory effect on ERK1/2 activity the loss of extracellular matrix was also reversed by PPADS. The action of PPADS seems to be due to a mechanism independent of P2 receptor antagonism.


Secondary omental torsion in children: report of two cases and review of the literature.
Torsion of the greater omentum (TGO) may be due to a congenital abnormal attachment of its free edge. There are no specific symptoms that allow a preoperative differential diagnosis of this condition from common pathologies such as acute appendicitis. Attachment of the omentum to the large bowel and the absence of concomitant diseases make it possible to distinguish TGO secondary to a congenital attachment anomaly from omental infarction, primary TGO, and TGO secondary to an acquired attachment anomaly (attachment to cysts, tumours, hernias, surgical scars, or perforated bowel segments). Resection of the ischaemic portion of the omentum permits complete resolution of the clinical symptoms. The authors report two cases of TGO in children due to abnormal attachment of the greater omentum to the ascending and transverse colon, respectively.


Discrimination and consistency of five myosin ATPase stains in human normal and Duchenne dystrophic muscle.
Limitations in the ability of the human visual system to assess accurately the relative staining densities of individual fibers in muscle tissue stained for myosin. ATPase can complicate the objective evaluation of fiber type populations. In this study a novel approach is employed which utilizes human visual capabilities to provide accurate fiber classification. Using this approach, the ability of five ATPase staining techniques to discriminate fiber type categories in single samples of human normal and Duchenne dystrophic skeletal muscle is evaluated, as is the consistency of the fiber type classifications between stains. While no major discrepancies in fiber typing were observed in the sample of normal muscle, significant differences in classification, along with a decrease in the ability to discriminate fiber types were noted in the sample of Duchenne muscular dystrophy. For the most part, these discrepancies were resolved by a re-interpretation of the staining characteristics of fibers in one stain.


Chromium contamination accentuates changes in the microbiome and heavy metal resistome of a tropical agricultural soil.
The impacts of hexavalent chromium (Cr) contamination on the microbiome, soil physicochemistry, and heavy metal resistome of a tropical agricultural soil were evaluated for 6 weeks in field-moist microcosms consisting of a Cr-inundated agricultural soil (SL9) and an untreated control (SL7). The physicochemistry of the two microcosms revealed a diminution in the total organic matter content and a significant dip in macronutrients phosphorus, potassium, and nitrogen concentration in the SL9 microcosm. Heavy metals analysis revealed the detection of seven heavy metals (Zn, Cu, Fe, Cd, Se, Pb, Cr) in the agricultural soil (SL7), whose concentrations drastically reduced in the SL9 microcosm. Illumina shotgun sequencing of the DNA extracted from the two microcosms showed the preponderance of the phyla, classes, genera, and species of Actinobacteria (33.11%), Actinobacteria_class (38.20%), Candidatus Saccharimonas (11.67%), and Candidatus Saccharimonas aalborgensis (19.70%) in SL7, and Proteobacteria (47.52%), Betaproteobacteria (22.88%), Staphylococcus (16.18%), Staphylococcus aureus (9.76%) in SL9, respectively. Functional annotation of the two metagenomes for heavy metal resistance genes revealed diverse heavy metal resistomes involved in the uptake, transport, efflux, and detoxification of various heavy metals. It also revealed the exclusive detection in SL9 metagenome of resistance genes for chromium (chrB, chrF, chrR, nfsA, yieF), cadmium (czcB/czrB, czcD), and iron (fbpB, yqjH, rcnA, fetB, bfrA, fecE) not annotated in SL7 metagenome. The findings from this study revealed that Cr contamination induces significant shifts in the soil microbiome and heavy metal resistome, alters the soil physicochemistry, and facilitates the loss of prominent members of the microbiome not adapted to Cr stress.


Neuropathic Pain Symptom Inventory (NPSI) Questionnaire-Persian Version Can Differentiate Neuropathic from Non-Neuropathic Pain.
Neuropathic pain (NP) is a common condition that impacts life negatively. This type of pain responds poorly to treatment. Neuropathic Pain Symptom Inventory (NPSI) is a common instrument used for the assessment of NP response to the treatment. The current study aims to validate the Persian version of NPSI (PV-NPSI). The current study has been conducted on 162 patients experiencing pain from neuropathic ornon-neuropathic origin. The Persian version of NPSI was proposed through standard protocol and responded to by patients twice: at baseline within an interval of 3 hours and then again within 1 month. Its correlation with the patient global impression of change (PGIC) and the clinical global impression of change (CGIC) was assessed. In addition, the validity and reliability of the PV-NPSI was evaluated. The reliability Cronbach's alpha of PV-NPSI was 0.834 and test-retest intraclass-coefficient was calculated as 0.983 (95% confidence interval [CI]: 0.977-0.988; p < .001). In addition, the measured coefficient sensitivity to change based on PGIC and CGIC was 0.859 for both. Receiver operating characteristic (ROC) curve for the diagnosis of NP revealed area under curve (AUC) of 0.936 (p < .001; 95%CI: 0.894-0.978). Based on the current study's findings, the PV-NPSI is a reliable and valid means for the differentiation of NP from the other types of pain in patients with several musculoskeletal pain complaints, but we cannot determine a cutoff point for it. Also, this questionnaire can be efficiently used for the assessment of response to NP treatment.


Results of flexor tendon tenolysis after replantation in the hand.
Thirty-seven replanted digital units and four thumb replantations had a flexor tendon tenolysis at an average of 10 months after replantation. The results were assessed by measuring total active motion, potential active motion, and by the formula of Strickland and associates. The total active motion increased from a mean pretenolysis of 72 degrees to 130 degrees. The potential active motion increased from a mean of 43% to 70% after tenolysis. Both of these improvements were statistically significant (p less than 0.001). The formula of Strickland and associates rated 13 excellent, 11 good, 6 fair, and 11 poor. The thumbs had two fair results and two poor results. Poor results were also seen in crush or avulsion amputations, hands with more than two digits amputated, and those requiring a proximal interphangeal joint capsulotomy. Little difference was found related to the number of arteries or tendons repaired. Complications included tendon rupture and infection. No digits were lost. The results of this study would support flexor tendon tenolysis after replantation of fingers but not replanted thumbs.


Long-term outcome and quality of care of patients with Staphylococcus aureus bacteremia.
To assess the long-term outcome and influence of clinical management of patients with Staphylococcus aureus bacteremia (SAB), 229 patients with blood cultures positive for Staphylococcus aureus between January 1997 and December 2000 were retrospectively identified and followed up. Risk factors, source of infection, treatment, clinical course, and outcome were recorded by chart review. For the assessment of 1-year survival, a questionnaire was sent to family doctors and government registration offices. Time of initial antibiotic therapy, duration of antibiotic treatment and performance of echocardiography were regarded as indicators of the quality of the clinical management of SAB. Among the 229 patients studied, 218 were evaluable for 1-year survival. Crude mortality after 1 year was 37.6% year. Within 30 days 43 (19.7%) patients had died, and 39 (17.9%) additional patients died thereafter. Using multivariate analysis, the following variables were associated with death: malignant disease (odds ratio [OR] 4.8; 95% confidence interval [CI], 2.6-8.9), pneumonia (OR, 3.6; 95%CI, 1.2-10.2), age >60 years (OR, 2.6; 95%CI, 1.5-4.5), and known source of infection (OR, 2.3; 95%CI, 1.3-4.1). Among 160 patients with a completely assessable treatment course 73 (46%) had received antibiotics for at least 14 days. A delay of antibiotic treatment of 1 day or more after microbiological diagnosis was observed in 28.3% of patients (i.e., 60 of 212 patients who received at least 1 dose of antibiotics). Echocardiography was performed in 101 (44.1%) cases. Overall, the findings indicate that standard guidelines for the management of SAB are followed only in part in clinical practice. In order to reduce the considerable mortality associated with SAB and to improve short- and long-term outcome, efforts should be made to increase adherence to recommendations.


Residual force enhancement is attenuated for quick stretch conditions.
It is generally accepted that the magnitude of residual force enhancement is not affected by stretching velocity. However, we recently found that when the stretching velocity was too large, the magnitude of residual force enhancement was attenuated or vanished in cat soleus muscle in situ. Therefore, the purpose of this study was to extend the knowledge by conducting very quick stretches in skinned rabbit psoas and soleus muscle fibers. Skinned psoas (N = 17) or soleus (N = 13) muscle fibers were activated isometrically at an average sarcomere length of 2.7 μm, and then, actively stretched to an average sarcomere length of 3.0 μm in 0.5 or 500 ms, followed by an isometric contraction at that length. In addition, a purely isometric reference contraction was conducted at an average sarcomere length of 3.0 μm to calculate the magnitude of residual force enhancement for both stretch velocities. The magnitude of residual force enhancement was significantly different between 0.5 ms stretch (101.5 ± 5.6% for psoas, and 101.5 ± 2.3% for soleus) and 500 ms stretch (106.2 ± 5.9% for psoas, and 106.8 ± 5.1% for soleus) while the magnitude of residual force enhancement was not significantly different between muscles. In line with our previous finding, the magnitude of residual force enhancement can vary when the stretch velocity is very large. This finding can contribute to clarify the key mechanism for inducing residual force enhancement and to explain contradicting results obtained in previous studies.


Rapid real-time PCR for determination of penicillin susceptibility in pneumococcal meningitis, including culture-negative cases.
A novel real-time PCR-hybridization assay was developed for the rapid (<1 h) detection of penicillin susceptibility in Streptococcus pneumoniae. When applied to 24 pneumococcal DNA-positive cerebrospinal fluid extracts, penicillin-sensitive S. pneumoniae was detected in all instances. Real-time PCR proved more sensitive than culture, microscopy, or antigen detection and provided susceptibility data even in culture-negative cases.


Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults.
Nephropathic cystinosis is a multisystem autosomal recessive disease caused by cystine accumulation, which is usually treated by oral cysteamine. In order to determine long-term effects of this therapy, we enrolled 86 adult patients (mean age 26.7 years) diagnosed with nephropathic cystinosis, 75 of whom received cysteamine. Therapy was initiated at a mean age of 9.9 years with a mean duration of 17.4 years. By last follow-up, 78 patients had end-stage renal disease (mean age 11.1 years), 62 had hypothyroidism (mean age 13.4), 48 developed diabetes (mean age 17.1 years), and 32 had neuromuscular disorders (mean age 23.3 years). Initiating cysteamine therapy before 5 years of age significantly decreased the incidence and delayed the onset of end-stage renal disease, and significantly delayed the onset of hypothyroidism, diabetes, and neuromuscular disorders. The development of diabetes and hypothyroidism was still significantly delayed, however, in patients in whom therapy was initiated after 5 years of age, compared with untreated patients. The life expectancy was significantly improved in cysteamine-treated versus untreated patients. Thus, cysteamine decreases and delays the onset of complications and improves life expectancy in cystinosis. Hence, cysteamine therapy should be introduced as early as possible during childhood and maintained lifelong.


The role of calcium crystals and their effect on osteoarthritis pathogenesis.
Osteoarthritis (OA) is a degenerative joint disease characterized by progressive degeneration of articular cartilage. Due to its high prevalence and limited treatment options, OA has become one of the most disabling diseases in developed countries. In recent years, OA has been recognized as a heterogenic disease with various phenotypes. Calcium crystal-related endotypes, which are defined by either a distinct functional or pathobiological mechanism, are present in approximately 60% of all OA patients. Two different calcium crystals can accumulate in the joint and thereby calcify the cartilage matrix, which are basic calcium phosphate (BCP) and calcium pyrophosphate (CPP) crystals. The formation of these crystals depends mainly on the balance of phosphate and pyrophosphate, which is regulated by specific proteins controlling the pyrophosphate metabolism. Dysregulation of these molecules subsequently leads to preferential formation of either BCP or CPP crystals. BCP crystals, on the one hand, are directly associated with OA severity and cartilage degradation. They are mostly located in the deeper cartilage layers and are associated with chondrocyte hypertrophy. CPP crystal deposition, on the other hand, is a hallmark of chondrocalcinosis and is associated with aging and chondrocyte senescence. Therefore, BCP and CPP crystals are associated with different chondrocyte phenotypes. However, BCP and CPP crystals are not mutually exclusive and can coexist in OA, creating a mixed endotype of OA. Both crystals clearly play a role in the pathogenesis of OA. However, the exact impact of each crystal type on either driving the disease progression or being a result of chondrocyte differentiation is still to be elucidated.


Pressure and doping effects on the structural stability of thermoelectric BaAg2Te2.
Ternary chalcogenides have attracted great attention for their potential applications in thermoelectric devices. Here, we investigate the pressure and doping effects on the structural stability of BaAg2Te2using first-principles calculations. Imaginary frequencies are observed in the calculated phonon dispersions of the reportedPnmastructure, indicating thatPnmaBaAg2Te2is lattice dynamically unstable at 0 K. Although the imaginary phonon frequencies are small, we find that hydrostatic pressure cannot effectively stabilize the structure. Based on the soft mode at Γ point, a new monoclinic phase with a space group ofP21/cis proposed. Fromab initiomolecular dynamics simulations, theP21/cphase is predicted to transform to thePnmaphase at a low temperature below 100 K. Electron/hole doping effects on the lattice dynamical stability of thePnmaphase are also studied. It is found that hole doping is superior to electron doping in stabilizing thePnmaphase. Further study on the electrical transport properties of thePnmaphase reveals a higher performance alongbaxis than that along the other two directions. This work paves an avenue to better understand the structural stability and electrical transport properties of thermoelectric BaAg2Te2.


Skin healing and collagen changes of rats after fractional erbium:yttrium aluminum garnet laser: observation by reflectance confocal microscopy with confirmed histological evidence.
The fractional erbium:yttrium aluminum garnet (Er:YAG) laser is widely applied. Microstructural changes after laser treatment have been observed with histopathology. Epidermal and dermal microstructures have also been analyzed using reflectance confocal microscopy (RCM). However, no studies have compared these two types of microstructural changes in the same subject at multiple time points after irradiation, and it is unclear if these two types of changes are consistent. We use RCM to observe the effect of different laser energies on skin healing and collagen changes in the skin of Sprague-Dawley rats that had been irradiated by fractional Er:YAG lasering at different energies. RCM was used to observe skin healing and detect collagen changes at different time points. Collagen changes were observed using hematoxylin and eosin (H&E) staining and quantitatively analyzed by western blot. RCM showed that, irrespective of laser energy, microscopic treatment zones (MTZs) were larger at 1 day after irradiation. The MTZs then reduced in size from 3 to 7 days after irradiation. The higher the energy, the larger the MTZ area. The amount of collagen also increased with time from 1 day to 8 weeks. However, the increase in the collagen amount on both RCM and H&E staining was not influenced by the laser energy. Western blotting confirmed that the amount of type I and type III collagens increased over time, but there were no significant differences between the different energy groups (p > 0.05). In conclusion, RCM is a reliable technique for observing and evaluating skin healing and collagen expression after laser irradiation.


[Comparative study of the differential susceptibility of different cell lines to pandemic H1N1v influenza viruses and avian influenza, swine influenza, and human influenza viruses].
The proliferation characteristics of influenza viruses of different origin were tested in various human and animal cell cultures. Pandemic H1N1v influenza and swine influenza viruses were shown to have a low infectious activity in virtually all the test lines. In spite of this, the replication of this group of viruses may be detected by de novo NP synthesis. These viruses are able to activate programmed cell death. Moreover, a low inoculative virus dose exerts a stimulating effect on cell proliferation in both suspension and monolayer cell lines.


Loneliness, depression, stress, and social supports in neglectful families.
Comparisons of neglectful with non-neglectful low-SES parents revealed that the neglectful parents reported more life stresses, greater depression and loneliness, and weaker informal social supports. In the neglectful families, loneliness was positively associated with life stresses and negatively associated with network supports, but not with caseworker-assessed social isolation.