The TRPV1 channel in rodents is a major target for antinociceptive effect of the probiotic Lactobacillus reuteri DSM 17938.
Certain probiotic bacteria have been shown to reduce distension-dependent gut pain, but the mechanisms involved remain obscure. Live luminal Lactobacillus reuteri (DSM 17938) and its conditioned medium dose dependently reduced jejunal spinal nerve firing evoked by distension or capsaicin, and 80% of this response was blocked by a specific TRPV1 channel antagonist or in TRPV1 knockout mice. The specificity of DSM action on TRPV1 was further confirmed by its inhibition of capsaicin-induced intracellular calcium increases in dorsal root ganglion neurons. Another lactobacillus with ability to reduce gut pain did not modify this response. Prior feeding of rats with DSM inhibited the bradycardia induced by painful gastric distension. These results offer a system for the screening of new and improved candidate bacteria that may be useful as novel therapeutic adjuncts in gut pain. Certain bacteria exert visceral antinociceptive activity, but the mechanisms involved are not determined. Lactobacillus reuteri DSM 17938 was examined since it may be antinociceptive in children. Since transient receptor potential vanilloid 1 (TRPV1) channel activity may mediate nociceptive signals, we hypothesized that TRPV1 current is inhibited by DSM. We tested this by examining the effect of DSM on the firing frequency of spinal nerve fibres in murine jejunal mesenteric nerve bundles following serosal application of capsaicin. We also measured the effects of DSM on capsaicin-evoked increase in intracellular Ca(2+) or ionic current in dorsal root ganglion (DRG) neurons. Furthermore, we tested the in vivo antinociceptive effects of oral DSM on gastric distension in rats. Live DSM reduced the response of capsaicin- and distension-evoked firing of spinal nerve action potentials (238 ± 27.5% vs. 129 ± 17%). DSM also reduced the capsaicin-evoked TRPV1 ionic current in DRG neuronal primary culture from 83 ± 11% to 41 ± 8% of the initial response to capsaicin only. Another lactobacillus (Lactobacillus rhamnosus JB-1) with known visceral anti-nociceptive activity did not have these effects. DSM also inhibited capsaicin-evoked Ca(2+) increase in DRG neurons; an increase in Ca(2+) fluorescence intensity ratio of 2.36 ± 0.31 evoked by capsaicin was reduced to 1.25 ± 0.04. DSM releasable products (conditioned medium) mimicked DSM inhibition of capsaicin-evoked excitability. The TRPV1 antagonist 6-iodonordihydrocapsaicin or the use of TRPV1 knock-out mice revealed that TRPV1 channels mediate about 80% of the inhibitory effect of DSM on mesenteric nerve response to high intensity gut distension. Finally, feeding with DSM inhibited perception in rats of painful gastric distension. Our results identify a specific target channel for a probiotic with potential therapeutic properties.


Role of transurethral resection of the prostate in population-based prostate cancer incidence rates.
The extensive pool of asymptomatic prostate disease in the population, which increases substantially with age, suggests that the frequent use of transurethral resection of the prostate (TURP) in recent decades has had a large effect on prostate cancer incidence. The authors identified the effect of TURP-detected prostate cancer on the observed incidence rates between 1973 and 1993 for men aged 65 years and older. They linked population-based cancer registry data from the Surveillance, Epidemiology, and End Results Program to Medicare records between 1986 and 1993 to determine whether a TURP occurred sufficiently close to the time of a prostate cancer diagnosis for them to assume that it led to the diagnosis. TURP-detected cases prior to 1986 were calculated using an indirect method that involved multiplying the TURP procedure rate in the general population (from the National Hospital Discharge Survey) by estimates of the proportion of TURPs resulting in a prostate cancer diagnosis (from Medicare data and the literature). TURP explained much of the observed increase in overall prostate cancer incidence between 1973 and 1986 and possibly all of it in men aged 70 years and older. However, its influence on the trend and overall magnitude of the rates diminished between 1987 and 1993. The changing role of TURP in detecting prostate cancer is attributed to changes in medical technology and screening practices. The declining influence of TURP on prostate cancer incidence is likely to have continued beyond the study period due to the recent introduction and increasing use of medications for treating obstructive uropathy.


Treatment continuation in patients receiving biological agents or conventional DMARD therapy.
To compare drug continuation rates in patients with rheumatoid arthritis who start on a biological agent and in a control group of patients with a change in disease modifying antirheumatic drug (DMARD) treatment after previous DMARD failure. Patients with rheumatoid arthritis enrolled in the German biologics register between May 2001 and September 2003 were included in the study. Data were available for 511 patients treated with etanercept, 343 with infliximab, 70 with anakinra, and 599 controls. Propensity scores were used to select a subsample of patients from the control group who were likely to be treated with biological agents because of their disease severity, as well as comparable infliximab and etanercept cases. Treatment continuation after 12 months was similar for etanercept (68.6% (95% confidence interval, 62% to 75%)) and infliximab (65.4% (58% to 73%)) but lower for anakinra (59% (41% to 77%)). Treatment continuation was more likely for patients on combinations of biological agents and DMARDs than for those on infliximab or etanercept alone. Patients treated with biological agents were more severely ill than those in the control group and had more previous DMARD failures. After adjustment for baseline differences, the continuation rates were higher in patients treated with biological agents than in comparable control patients treated with leflunomide or leflunomide/methotrexate. Treatment continuation of biological agents in clinical practice is less likely than in randomised clinical trials but more likely than in comparable controls treated with conventional DMARDs.


Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.
Over half of mitochondrial proteins are imported from the cytosol via the pre-sequence pathway, controlled by the TOM complex in the outer membrane and the TIM23 complex in the inner membrane. The mechanisms through which proteins are translocated via the TOM and TIM23 complexes remain unclear. Here we report the assembly of the active TOM-TIM23 supercomplex of Saccharomyces cerevisiae with translocating polypeptide substrates. Electron cryo-microscopy analyses reveal that the polypeptide substrates pass the TOM complex through the center of a Tom40 subunit, interacting with a glutamine-rich region. Structural and biochemical analyses show that the TIM23 complex contains a heterotrimer of the subunits Tim23, Tim17 and Mgr2. The polypeptide substrates are shielded from lipids by Mgr2 and Tim17, which creates a translocation pathway characterized by a negatively charged entrance and a central hydrophobic region. These findings reveal an unexpected pre-sequence pathway through the TOM-TIM23 supercomplex spanning the double membranes of mitochondria.


CO2 and compressive immobilization of C. elegans on-chip.
We present two microfluidic approaches for immobilizing the roundworm C. elegans on-chip. The first approach creates a CO(2) micro-environment while the second one utilizes a deformable PDMS membrane to mechanically restrict the worm's movement. An on-chip 'behavior' module was used to characterize the effect of these methods on the worm's locomotion pattern. Our results indicate that both methods are appropriate for the short-term (minutes) worm immobilization. The CO(2) method offers the additional advantages of long-term immobilization (1-2 hours) and reduced photobleaching, if fluorescent imaging during immobilization is required. We envision the use of these methods in a wide variety of biological studies in C. elegans, including cell developmental and neuronal regeneration studies.


Mother and father self-reports of corporal punishment and severe physical aggression toward clinic-referred youth.
Examined the extent to which 359 mothers and 140 fathers of clinic-referred youth (ages 2 to 17) reported using corporal punishment and severe physical aggression when asked directly via intake screening questionnaires at a community mental health center; higher prevalence rates emerged compared to families in the general population. Clinic-referred parents reported greater use of corporal punishment for younger relative to older youth, sons relative to daughters, and by single relative to married mothers. In cases with reports from both parents, mothers used corporal punishment more frequently than fathers. Demographic factors were not linked to severe physical aggression, except for mothers' treatment of sons versus daughters. After controlling for demographic factors, maternal and paternal reports of child externalizing behavior accounted for significant variance in their own and their partner's use of corporal punishment, and in mothers' use of severe physical aggression.


General intelligence in another primate: individual differences across cognitive task performance in a New World monkey (Saguinus oedipus).
Individual differences in human cognitive abilities show consistently positive correlations across diverse domains, providing the basis for the trait of "general intelligence" (g). At present, little is known about the evolution of g, in part because most comparative studies focus on rodents or on differences across higher-level taxa. What is needed, therefore, are experiments targeting nonhuman primates, focusing on individual differences within a single species, using a broad battery of tasks. To this end, we administered a large battery of tasks, representing a broad range of cognitive domains, to a population of captive cotton-top tamarin monkeys (Saguinus oedipus). Using a Bayesian latent variable model, we show that the pattern of correlations among tasks is consistent with the existence of a general factor accounting for a small but significant proportion of the variance in each task (the lower bounds of 95% Bayesian credibility intervals for correlations between g and task performance all exceed 0.12). Individual differences in cognitive abilities within at least one other primate species can be characterized by a general intelligence factor, supporting the hypothesis that important aspects of human cognitive function most likely evolved from ancient neural substrates.


Atypical Hidradenoma Mimicking Primary Mammary Carcinoma on Breast Fine-Needle Aspiration: A Case Report with Long-Term Follow-Up.
Fine-needle aspiration (FNA) is well-established as an accurate technique for the diagnosis of palpable breast masses. While the differential diagnosis of such lesions usually focuses on benign or malignant mammary proliferations, a subset of breast neoplasms arises from skin and soft tissue. Skin adnexal neoplasms such as hidradenoma can pose a particular pitfall on breast FNA cytology (FNAC) as epithelial proliferations that are not of ductal or lobular origin. A 59-year-old female presented with a superficial breast mass. FNAC revealed a hypercellular lesion with marked nuclear atypia that was highly suspicious for carcinoma. However, at partial mastectomy, the histological features of the tumor were consistent with atypical hidradenoma. Negativity for estrogen receptor (ER) and progesterone receptor (PR) confirmed the diagnosis. Eighteen years later, the patient remains free of recurrence or metastasis. This report offers the first description of findings of atypical hidradenoma on FNAC. In the breast, its high cellularity and nuclear atypia can mimic a primary mammary carcinoma on FNAC. Although breast and skin adnexal tumors show a immunohistochemical overlap, negative ER and PR stains in a low-grade tumor can suggest a nonmammary lesion. Skin adnexal neoplasms should be considered in the differential diagnosis of superficial breast tumors.


Effects of temperature on the recovery of juvenile grayling (Thymallus thymallus) from exposure to Al+Fe.
One-summer-old graylings (Thymallus thymallus) were exposed for 6 days to water containing a mixture of 1 mg l(-1) Fe and 100 microg l(-1) Al at pH 5.5, with or without 15 mg l(-1) humic acid. A pH of 6.9 was used as a control. The experiment was performed at two test temperatures, 13 and 3 degrees C. After 1 week of exposure, half of the fish in the tank were taken for oxygen measurement and tissue sampling. The remaining half were maintained in metal-free water for a further week to assess their recovery at the two test temperatures. Fifty percent of the fish died under metal exposure at 13 degrees C, but none at 3 degrees C. Despite of the lack of mortalities at the lower temperature, surviving fish at both test temperatures suffered similar gill damage (adherence of lamellae), disturbances in ion regulation, increases in haematocrit value (Hct) and haemoglobin (Hb) concentration and reductions in oxygen consumption. The addition of humic acid prevented these changes. The reduced plasma chloride concentration, increased blood Hct value and Hb concentration recovered completely at 13 degrees C, whereas the lowered oxygen consumption recovered less completely, which may be attributed to the remaining minor gill damage (lamellar hypertrophy). At the lower temperature, the adherence of lamellae persisted after the recovery period, and oxygen consumption, therefore, remained at a very low level. The decreased plasma chloride concentration was also unable to recover. The accumulation of Al inside the gill tissue was greater at low temperature. We conclude that the acute toxicity of a mixture of Fe and Al to grayling and their subsequent ability to recovery is dependent on the exposure temperature.


Differential diagnosis of severe cutaneous drug eruptions.
Adverse cutaneous reactions to drugs are frequent, mostly secondary to antibacterials, however, serious adverse cutaneous reactions are infrequent. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of the same disease. They are the more severe drug eruptions, with a mortality around 30% for TEN. The confusion between erythema multiforme major and SJS means that erythema multiforme major is the main differential diagnosis. Skin disorders involving desquamation, in particular after pustulosis, are also common differential diagnoses. Mechanical or autoimmune blistering are also potential misdiagnoses of TEN/SJS. Hypersensitivity Syndrome (HSS) or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) is a severe cutaneous drug reaction with often a long duration of eruption and serious other organ involvement. Exfoliative dermatitis, whether caused by psoriasis, dermatitis or lymphoma, can be thought of as a differential diagnosis of DRESS/HSS. Angio-immunoblastic lymphadenopathy, viral eruption and vasculitis are other differential diagnoses of DRESS/HSS. Prompt recognition of a severe drug reaction and withdrawal of the culprit drug is often the most important therapeutic action. Alternatively, a delay in starting a specific treatment for a disease misdiagnosed as a drug eruption could be deleterious.


Identification of a novel class of mammalian phosphoinositol-specific phospholipase C enzymes.
Phosphoinositol (PhoIns)-specific phospholipase C enzymes (PLCs) are central to the inositol lipid signaling pathways and contribute to intracellular Ca2+ release and protein kinase C activation. Five distinct classes of PhoIns-specific PLCs are known to exist in mammals, which are activated by membrane receptor-mediated events. Here we have identified a sixth class of PhoIns-specific PLC with a novel domain structure, which we have termed PLC-eta. Two putative PLC-eta enzymes were identified in humans and in mice. Sequence analysis revealed that residues implicated in substrate binding and catalysis from other PhoIns-specific PLCs are conserved in the novel enzymes. PLC-eta enzymes are most closely related to the PLC-delta class and share a close evolutionary relationship with other PLC isozymes. EST analysis and RT-PCR data suggest that PLC-eta enzymes are expressed in several cell types and, by analogy with other mammalian PhoIns-specific PLCs, are likely to be involved in signal transduction pathways.


Adult Attention-Deficit/Hyperactivity Disorder and the Risk of Dementia.
Evidence that adult attention-deficit/hyperactivity disorder (ADHD) is associated with an increased risk of dementia is scarce and inconsistent, and potential sources of bias are untested. To examine the association between adult ADHD and the risk of dementia. This prospective national cohort study consisted of 109 218 members of a nonprofit Israeli health maintenance organization born between 1933 and 1952 who entered the cohort on January 1, 2003, without an ADHD or dementia diagnosis and were followed up to February 28, 2020. Participants were aged 51 to 70 years in 2003. Statistical analysis was conducted from December 2022 to August 2023. Adult ADHD was a time-varying covariate, classified as present from the age of the first diagnosis (using the International Classification of Diseases, Ninth Revision, and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision); otherwise, absent. Cox regression models were fitted to quantify the association between adult ADHD and the risk of incident dementia with hazard ratios (HRs) and their 95% CIs unadjusted and in the primary analysis, using inverse probability weights, adjusted for 18 sources of potential confounding. In 14 complementary analyses, subgroup and sensitivity analyses were implemented. At the beginning of the follow-up, the sample of 109 218 participants had a mean (SD) age of 57.7 (5.5) years, 56 474 participants (51.7%) were female, and 52 744 (48.3%) were male. During follow-up, 730 participants (0.7%) received a diagnosis of adult ADHD, and 7726 (7.1%) received a diagnosis of dementia. Dementia occurred among 96 of 730 participants (13.2%) with adult ADHD and 7630 of 108 488 participants (7.0%) without adult ADHD. In the primary analysis, compared with the absence of adult ADHD, the presence of adult ADHD was statistically significantly (P < .001) associated with an increased dementia risk (unadjusted HR, 3.62 [95% CI, 2.92-4.49; P < .001]; adjusted HR, 2.77 [95% CI, 2.11-3.63; P < .001]). Twelve of the 14 complementary analyses did not attenuate the conclusions based on the results of the primary analysis. There was, however, no clear increase in the risk of dementia associated with adult ADHD among those who received psychostimulant medication, and evidence of reverse causation was mild. In this cohort study of individuals born between 1933 and 1952 and followed up in old age, adult ADHD was associated with an increased risk of dementia. Policy makers, caregivers, patients, and clinicians may wish to monitor reliably for ADHD in old age.


Generation of flagella by cultured mouse spermatids.
During the short-term culturing of mouse spermatogenic cells, flagella were generated by round spermatids previously lacking tails. Unseparated germ cells were obtained by enzymatic treatments and round spermatids (greater than 90% pure) were purified by unit gravity sedimentation. As determined by Nomarski or phase-contrast microscopy, no cells had flagella immediately after isolation; flagella were first clearly detected after 6 1/2 h of culture in Eagle's minimal essential medium containing 10% fetal bovine serum and 6 mM lactate. After 24 h, approximately 20% of round spermatids had formed flagella. Multinucleated round spermatids often formed multiple flagella, the number never exceeding the number of nuclei per symplast. Round spermatids were the only spermatogenic cells capable of tail formation. Flagella elongation was blocked by 1 microM demecolcine, an inhibitor of tubulin polymerization. Indirect immunofluorescence localized tubulin in the flagella. As seen by scanning electron microscopy, flagella developed as early as 2 h after culture and continued to elongate over the next 20 h, reaching lengths of at least 19 micron. Transmission electron microscopy demonstrated that flagella formed in culture resembled flagella from Golgi-phase round spermatids in situ; the flagella consisted of "9+2" axonemes lacking other accessory structures such as outer dense fibers and the fibrous sheath. As determined by acridine orange staining of the developing acrosomes, all spermatids that formed flagella in culture were Golgi-phase spermatids. By these criteria, the structures are indeed true flagella, corresponding in appearance to what others have described for early mammalian spermatid flagella in situ. We believe this is the first substantiated report of limited in vitro differentiation by isolated mammalian spermatids.


Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis.
Impaired invasion of extravillous trophoblasts and severe oxidative stress manifest the poor placentation in preeclampsia, which is life-threatening and more than a hypertensive disease of pregnancy. Previous studies have reported that G protein-coupled receptor kinases (GRKs) play a key role in initiating hypertension and hypertensive renal damage, yet little evidence so far suggests a link between GRKs and preeclampsia-related hypertension. Here, we demonstrate GRK2 expression is significantly downregulated (P < 0.0001) in preeclamptic placentae compared to normotensive controls. Knockdown or inhibition of GRK2 in placentae caused insufficient arterial remodeling and elevated trophoblast necroptosis in vivo. These further induced preeclampsia-like phenotype in mice: hypertension, proteinuria, and elevated pro-angiogenic cytokines. By human extra-villous invasive trophoblast cell line (HTR8/SVneo cells), we revealed the knockdown or inhibition of GRK2 triggered excessive death with typical necroptotic characteristics: nuclear envelope rupture and the activation of RIPK1, RIPK3, and MLKL. Necrostatin-1, an inhibitor of RIPK1, is able to restore the survival of trophoblasts. Together, our findings demonstrated that insufficient GRK2 activity compromises spiral artery remodeling and initiates necrotic events in placentae, thereby leading to preeclampsia. These findings advance our understanding of GRK2 in the pathogenesis of preeclampsia and could shed light on a potential treatment for preeclampsia.


At the Bench: Preclinical rationale for exploiting NK cells and γδ T lymphocytes for the treatment of high-risk leukemias.
NK cells and γδ T lymphocytes display potent cytolytic activity against leukemias and CMV-infected cells and are thus, promising immune effector cells in the context of allo-HSCT. NK cells express HLA class I-specific inhibitory receptors and preferentially kill HLA class I(low) tumors or virus-infected cells. Killing occurs upon engagement of activating NKRs with ligands that are up-regulated on tumors and infected cells. A similar activating receptor/ligand interaction strategy is used by γδ T cells, which in addition, use their TCRs for recognition of phosphorylated antigens and still largely undefined ligands on tumor cells. In the haploidentical allo-HSCT setting, alloreactive NK cells, derived from donor HSCs, can exert potent antileukemia activity and kill residual patient DCs and T cells, thus preventing GvHD and graft rejection. However, generation of KIR(+) alloreactive NK cells from HSCs requires many weeks, during which leukemia relapses, and life-threatening infections may occur. Importantly, mature NK cells and γδ T cells can control certain infectious agents efficiently, in particular, limit CMV reactivation, and infusion of such donor cells at the time of HSCT has been implemented. Development of novel, cell-based immunotherapies, allowing improved trafficking and better targeting, will endow NK cells and γδ T lymphocytes with enhanced anti-tumor activity, also making them key reagents for therapies against solid tumors. The clinical aspects of using NK cells and γδ T lymphocytes against hematological malignancies, including the allo-HSCT context, are reviewed in the related side-by-side paper by Locatelli and colleagues [1].


Application of multi-correlation-scale measurement matrices in ghost imaging via sparsity constraints.
Sampling and reconstruction techniques are of special interest and importance in ghost imaging. Up to now, the transverse correlation scale of measurement matrices are usually constant. This paper explores a new possibility of constructing highly efficient measurement matrices with multi-correlation scales. Comparisons between the simulational and experimental results show that the multi-correlation-scale measurement matrices are highly efficient and accurate in sampling and image reconstruction and have a better antinoise ability than the existing constant-correlation-scale measurement matrices.


Inhibition of blue light-dependent H+ pumping by abscisic acid through hydrogen peroxide-induced dephosphorylation of the plasma membrane H+-ATPase in guard cell protoplasts.
Blue light (BL)-dependent H+ pumping by guard cells, which drives stomatal opening, is inhibited by abscisic acid (ABA). We investigated this response with respect to the activity of plasma membrane H+-ATPase using Vicia guard cell protoplasts. ATP hydrolysis by the plasma membrane H+-ATPase, phosphorylation of the H+-ATPase, and the binding of 14-3-3 protein to the H+-ATPase stimulated by BL were inhibited by ABA at 10 microm. All of these responses were similarly inhibited by hydrogen peroxide (H2O2) at 1 mm. The ABA-induced inhibitions of BL-dependent H+ pumping and phosphorylation of the H+-ATPase were partially restored by ascorbate, an intracellular H2O2 scavenger. A single-cell analysis of the cytosolic H2O2 using 2',7'-dichlorofluorescin revealed that H2O2 was generated by ABA in guard cell protoplasts. We also indicated that H+ pumping induced by fusicoccin and the binding of 14-3-3 protein to the H+-ATPase were inhibited slightly (approximately 20%) by both ABA and H2O2. By contrast, H2O2 at 1 mm did not affect H+ pumping by the H+-ATPase in microsomal membranes. From these results, we concluded that inhibition of BL-dependent H+ pumping by ABA was due to a decrease in the phosphorylation levels of H+-ATPase and that H2O2 might be involved in this response. Moreover, there are at least two inhibition sites by ABA in the BL signaling pathway of guard cells.


Palliative care physicians' religious / world view and attitude towards euthanasia: a quantitative study among flemish palliative care physicians.
To Study the religious and ideological views and practice of Palliative Care physician towards Euthanasia. An anonymous self administered questionnaire approved by Flemish Palliative Care Federation and its ethics steering group was sent to all physicians(n-147) working in Flemish Palliative Care. Questionnaire consisted of three parts. In first part responded were requested to provide demographic information. In second part the respondents were asked to provide information concerning their religion or world view through several questions enquiring after religious or ideological affiliation, religious or ideological self-definition, view on life after death, image of God, spirituality, importance of rituals in their life, religious practice, and importance of religion in life. The third part consisted of a list of attitudinal statements regarding different treatment decisions in advanced disease on which the respondents had to give their opinion using a five-point Likert scale.99 physician responded. WE WERE ABLE TO DISTINGUISH FOUR CLUSTERS: Church-going physicians, infrequently church-going physicians, atheists and doubters. We found that like the Belgian general public, many Flemish palliative care physicians concoct their own religious or ideological identity and feel free to drift away from traditional religious and ideological authorities. In our research we noted that physicians who have a strong belief in God and express their faith through participation in prayer and rituals, tend to be more critical toward euthanasia. Physicians who deny the existence of a transcendent power and hardly attend religious services are more likely to approve of euthanasia even in the case of minors or demented patients. In this way this study confirms the influence of religion and world view on attitudes toward euthanasia.


Adenotonsillectomy for Snoring and Mild Sleep Apnea in Children: A Randomized Clinical Trial.
The utility of adenotonsillectomy in children who have habitual snoring without frequent obstructive breathing events (mild sleep-disordered breathing [SDB]) is unknown. To evaluate early adenotonsillectomy compared with watchful waiting and supportive care (watchful waiting) on neurodevelopmental, behavioral, health, and polysomnographic outcomes in children with mild SDB. Randomized clinical trial enrolling 459 children aged 3 to 12.9 years with snoring and an obstructive apnea-hypopnea index (AHI) less than 3 enrolled at 7 US academic sleep centers from June 29, 2016, to February 1, 2021, and followed up for 12 months. Participants were randomized 1:1 to either early adenotonsillectomy (n = 231) or watchful waiting (n = 228). The 2 primary outcomes were changes from baseline to 12 months for caregiver-reported Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite (GEC) T score, a measure of executive function; and a computerized test of attention, the Go/No-go (GNG) test d-prime signal detection score, reflecting the probability of response to target vs nontarget stimuli. Twenty-two secondary outcomes included 12-month changes in neurodevelopmental, behavioral, quality of life, sleep, and health outcomes. Of the 458 participants in the analyzed sample (231 adenotonsillectomy and 237 watchful waiting; mean age, 6.1 years; 230 female [50%]; 123 Black/African American [26.9%]; 75 Hispanic [16.3%]; median AHI, 0.5 [IQR, 0.2-1.1]), 394 children (86%) completed 12-month follow-up visits. There were no statistically significant differences in change from baseline between the 2 groups in executive function (BRIEF GEC T-scores: -3.1 for adenotonsillectomy vs -1.9 for watchful waiting; difference, -0.96 [95% CI, -2.66 to 0.74]) or attention (GNG d-prime scores: 0.2 for adenotonsillectomy vs 0.1 for watchful waiting; difference, 0.05 [95% CI, -0.18 to 0.27]) at 12 months. Behavioral problems, sleepiness, symptoms, and quality of life each improved more with adenotonsillectomy than with watchful waiting. Adenotonsillectomy was associated with a greater 12-month decline in systolic and diastolic blood pressure percentile levels (difference in changes, -9.02 [97% CI, -15.49 to -2.54] and -6.52 [97% CI, -11.59 to -1.45], respectively) and less progression of the AHI to greater than 3 events/h (1.3% of children in the adenotonsillectomy group compared with 13.2% in the watchful waiting group; difference, -11.2% [97% CI, -17.5% to -4.9%]). Six children (2.7%) experienced a serious adverse event associated with adenotonsillectomy. In children with mild SDB, adenotonsillectomy, compared with watchful waiting, did not significantly improve executive function or attention at 12 months. However, children with adenotonsillectomy had improved secondary outcomes, including behavior, symptoms, and quality of life and decreased blood pressure, at 12-month follow-up. ClinicalTrials.gov Identifier: NCT02562040.


An analysis of the inter-relationships among multiple bronchoalveolar lavage and serum determinations, physiologic tests, and clinical disease activity in patients with sarcoidosis.
Analysis of epithelial lining fluid from the lungs of patients with sarcoidosis frequently suggests the presence of an alveolitis. Several markers of this inflammatory response were quantitated in bronchoalveolar lavage fluid and serum from 45 non-smoking patients with sarcoidosis. All markers were elevated significantly compared to those from 19 normal controls. The degree of statistical correlation among all data was assessed. Pulmonary function tests, 67Gallium lung scans, and a clinical index of disease activity also were quantitated. When patients were grouped by the number of abnormal BAL lavage and serum markers, those patients with elevated values of five or more of these markers had significantly worse clinical disease and lower carbon monoxide diffusing capacities. These results indicate that pulmonary sarcoidosis is an immunologically heterogeneous disease and that measurement of several markers of disease activity may be required to accurately estimate the activity of the lung disease.


Suppression of the hypomethylated Moloney leukemia virus genome in undifferentiated teratocarcinoma cells and inefficiency of transformation by a bacterial gene under control of the long terminal repeat.
The Moloney leukemia virus (M-MuLV) genome was introduced into undifferentiated teratocarcinoma cells by transfection of a plasmid with the virus genome linked to pSV2neo, which carries a bacterial drug resistance gene, neo, or by cotransfection with pSV2neo. In the resulting cells, the M-MuLV genome remained hypomethylated, but its expression was suppressed in cells in an undifferentiated state. The pattern of DNA methylation of the viral genome remained unchanged when the cells were induced to differentiate into epithelial tissues. However, spontaneous M-MuLV expression was detected with differentiation of the cells. To determine to what extent the viral long terminal repeat (LTR) was responsible for this suppression in undifferentiated cells, I constructed plasmids in which neo was placed under the control of the promoter sequence of the dihydrofolate reductase gene or the M-MuLV LTR, and compared the biological activities of the plasmids in Ltk- cells and in undifferentiated teratocarcinoma cells. In Ltk- cells, these plasmids were highly efficient in making the cells resistant to selection by G418. However, in undifferentiated teratocarcinoma cells, the M-MuLV LTR promoted neo gene expression at only 10% of the expected efficiency, as compared with the expression of the neo gene under the control of the simian virus to or dihydrofolate reductase promoter. Thus, the mechanisms of gene regulation are not the same in undifferentiated and differentiated teratocarcinoma cells.


Randomized clinical trial of a diagnostic instrument for pain complaints.
This study evaluated use of the patient-administered Personal Pain Tracker in ambulatory primary care practice and tested the hypothesis that use of the instrument is associated with greater patient satisfaction with physician-patient communication regarding pain. This randomized clinical trial was conducted in the offices of 12 family physicians practicing in Los Angeles and Orange Counties in Southern California. Study subjects consisted of 79 patients who presented with pain complaints during the study's enrollment period and who conformed to the inclusion and exclusion criteria. Patients randomized to the experimental arm of the study received and completed the Pain Tracker, and both these patients and control group patients participated in a telephone interview with an investigator 1 week subsequent to their visit. Regardless of the specific nature or cause of their pain, patients randomized to the Pain Tracker group were substantially more likely to report that their physicians felt that their pain was genuine and were concerned about it, asked enough questions about the pain and listened carefully, gave them a chance to provide a complete explanation, and performed a thorough examination. Patients in the Pain Tracker group also reported a higher level of overall satisfaction with their visit. Use of the Pain Tracker instrument improves patients' perceptions of the quality of physician-patient communication regarding pain complaints and results in greater overall satisfaction with medical visits.


Hepatic artery infusion chemotherapy for colorectal liver metastases.
Twenty-two patients with hepatic colorectal metastases had Infusaid pumps implanted for hepatic artery infusion chemotherapy, or HAIC. Prior to pump placement, 19 of the 22 patients received percutaneous HAIC with 5-fluorouracil and citrovorum factor. Floxuridine, 0.2 mg/kg/d, was administered via the Infusaid pump and was alternated with saline solution every 2 weeks. HAIC responsiveness was defined as a 50% or greater reduction in the sum of all diameters of measured lesions on computerized tomography scans and no evidence of extra-hepatic tumor. Nine patients (41%) had a favorable response to HAIC; four (18%) had a partial response to percutaneous HAIC and five (23%) were considered pump responders. All responders had pretreatment liver replacement of less than 50%. The mean survival after pump placement was 13.6 months for responders and 11.1 months for non-responders. Although there were no operative deaths, the morbidity rate was 36%, and 31% of patients manifested significant chemotherapy toxicity. While toxicity is not insignificant and there is no survival benefit, the Infusaid pump is a reliable drug delivery system for HAIC, and may result in regression of colorectal liver metastases in patients with less than 50% hepatic replacement.


CT sialography, Part II: Parotid masses.
The advent of CT sialography has significantly altered the investigation of parotid masses. Conventional radiography had been limited by its inability to display soft tissue detail. While CT demonstrated soft tissue structures extremely well, limitations to visualizing parotid parenchyma itself were noted. Many of these limitations could be resolved if a sialographic contrast medium were utilized. Mass lesions can be directly visualized, such that size, location, and extent can be noted. Extrinsic or intrinsic etiology can be assessed. Descriptions of tumor morphology may be related to clinical aggressiveness. Mass locations may be correlated to the facial nerve and surgical landmarks. Adjacent tissue planes and lymph nodes are assessed. Examples of various types of parotid masses are illustrated.


[The therapeutic compliance in solid organ transplantation. The case of renal transplantation].
A successful transplantation implies that immunosuppressive drugs will have to be taken during the whole patient's life. Poor drug compliance is a multifactorial problem, that is particularly dangerous in organ transplantation as it can lead to loss of graft function and return to dialysis treatment. The medical doctor must stimulate the patient's adherence to the strict therapeutic drug protocol. The patient must also be reminded at each medical consultation of the importance of such rigorous drug intake. This bad (or non) compliance is particularly well demonstrated a long time after transplantation. The medical staff, all the health participants, but also the family members must continuously fight against non compliance, which is inherent to any chronic disease.


Does exercise training change physical activity in people with COPD? A systematic review and meta-analysis.
A systematic review and meta-analysis was conducted to examine the effect of exercise training on daily physical activity (PA) in people with chronic obstructive pulmonary disease (COPD). MEDLINE, PubMed, EMBASE, CINAHL, Physiotherapy Evidence Database (PEDro) and Cochrane Central Register of Controlled Trials were searched from their inception to week 27 of 2010, using the keywords 'COPD,' 'exercise,' 'therapy' and 'physical activity.' All studies except case reports were eligible for inclusion provided they investigated the effects of ≥4 weeks of supervised exercise training on PA in patients with COPD. Study quality for the randomised trials (RTs) and single-group interventional studies was rated using the PEDro scale and Downs and Black Tool, respectively. No randomised controlled trials met our study criteria. The two RTs had a mean PEDro score of 5. The 5 single-group studies had a mean Downs and Black score of 19 ± 3. When combined, a small effect on PA outcomes was demonstrated (overall mean effect = 0.12; p = 0.01). Taken together, the RTs and single-group studies demonstrate that exercise training may confer a significant but small increase in PA.


Large granular lymphocytes in human peripheral blood: ultrastructural and cytochemical characterization of the granules.
Large granular lymphocytes (LGL) are defined as nonadherent mononuclear cells with cytoplasmic azurophilic granules, avid receptors for the Fc portion of IgG, and cytotoxic functions (NK or ADCC activities). In the present study, the granules of LGL isolated from human peripheral blood have been analyzed by enzyme cytochemistry and electron microscopy. It had been found that: (1) in the single cells, granules at different stages of maturation could be detected: in addition, packaging of the granules took place in the proximity of the Golgi apparatus, which is similar to that seen in secretory cell types. (2) Acid phosphatase (AP) was observed within the granules and the vesicles located in the Golgi area: the Golgi apparatus identified through its thiamine pyrophosphatase-positivity was consistently negative for AP. (3) Alpha naphthyl-acetate esterase (ANAE) activity was localized in the granules as well as on the membrane of LGL and monocytes. (4) The ANAE activity of LGL was of the monocytic and not of the lymphocytic type, as shown by NaF inhibition. (5) The LGL granules, although identifiable as primary lysosomes, were not involved in the process of phagocytosis, since LGL failed consistently to ingest latex particles or opsonized red cells.


Emerging Role of CaV1.2 Channels in Proliferation and Migration in Distinct Cancer Cell Lines.
Extensive research is currently underway, seeking better diagnostic methods and treatments and a better understanding of the molecular mechanisms involved in cancer, from the role of specific genetic mutations to the intricate biochemical and molecular pathways involved. Because of their role in regulating relevant physiological events such as cell proliferation, migration, and invasion, ion channels have recently been recognized as important elements in cancer initiation and progression. Moreover, it has been reported that pharmacological intervention in ion channel activity might provide protection against diverse types of cancer, and that ion channels could be used as targets to counteract tumor growth, prevent metastasis, and overcome the therapy resistance of tumor cells. In this context, Ca2+ channels have been found to play a role in tumorigenesis and tumor progression. Specifically, L-type Ca2+ channel inhibition may affect cell proliferation, differentiation, and apoptosis. This review aims to provide insights into the potential role of these channels in cancer cell lines, emphasizing their participation in cell proliferation, migration, and autophagy induction, as well as their potential as rational targets for new cancer therapeutics.


Patient-reported 28 swollen and tender joint counts accurately represent RA disease activity and can be used to assess therapy responses at the group level.
Formal joint assessments are critically important to improve rheumatological care of patients with RA. The aim of this study was to determine the usefulness of patient-recorded 28 tender joint counts (TJCs) and swollen joint counts (SJCs) using a tablet personal computer and to explore the possibility of using patient-recorded data to calculate 28-joint DAS (DAS-28) and EULAR response. Forty-seven patients were included before initiation of adalimumab therapy and assessed at baseline and after 3 months. SJC and TJC were registered by the patients and thereafter by an experienced rheumatology specialist. Changes were correlated using Spearman's rank correlation test. The correlations between SJC and TJC derived by the physician and the patient at baseline were excellent (r = 0.78 and 0.87, respectively P < 0.01 for both). After 3 months, the correlations were less strong (0.645 and 0.745, respectively, P < 0.001 for both). When using the patient-derived SJC/TJC for calculation of the DAS-28 (patDAS-28), similar values were obtained, and correlations between DAS-28 and patDAS-28 were excellent (r = 0.91 at baseline, r = 0.90 at 3 months). According to the EULAR response criteria, the percentage of responders at the group level was nearly identical, although there was some disagreement at the individual level when DAS-28 and patDAS-28 were used to determine response to therapy. Patient-reported SJC and TJC can in research settings be used instead of physician-reported ones. Patient-derived SJC and TJC may also make it possible for rheumatologists to obtain quantitative joint count recordings much more frequently than is feasible for traditional joint counts.


Copper(II) complexes of pyridyl-appended diazacycloalkanes: synthesis, characterization, and application to catalytic olefin aziridination.
As part of an ongoing effort to rationally design new copper catalysts for olefin aziridination, a family of copper(II) complexes derived from new tetradentate macrocyclic ligands are synthesized, characterized both in the solid state and in solution, and screened for catalytic nitrene transfer reactivity with a representative set of olefins. The pyridylmethyl-appended diazacycloalkane ligands L6(py)2, L7(py)2, and L8(py)2 are prepared by alkylation of the appropriate diazacycloalkane (piperazine, homopiperazine, or diazacyclooctane) with picolyl chloride in the presence of triethylamine. The ligands are metalated with Cu(ClO4)(2).6H2O to provide the complexes [(L6(py)2)Cu(OClO3)]ClO4 (1), [(L7(py)2)Cu(OClO3)]ClO4 (2), and [(L8(py)2)Cu](ClO4)2 (3), which, after metathesis with NH4PF6 in CH3CN, afford [(L6(py)2)Cu(CH3CN)](PF6)2 (4), [(L7(py)2)Cu(CH3CN)](PF6)2 (5), and [(L8(py)2)Cu](PF6)2 (6). All six complexes are characterized by X-ray crystallography, which reveals that complexes supported by L6(py)2 and L7(py)2 (1, 2, 4, 5) adopt square-pyramidal geometries, while complexes 3 and 6, ligated by L8(py)2 feature tetracoordinate, distorted-square-planar copper ions. Tetragonal geometries in solution and d(x2 - y2), ground states are confirmed for the complexes by a combination of UV-visible and EPR spectroscopies. The divergent flexibility of the three supporting ligands influences the Cu(II)/Cu(I) redox potentials within the family, such that the complexes supported by the larger ligands L7(py)2 and L8(py)2 (5 and 6) exhibit quasi-reversible electron transfer processes (E1/2 approximately -0.2 V vs Ag/AgCl), while the complex supported by L6(py)2 (4), which imposes a rigid tetragonal geometry upon the central copper(II) ion, is irreversibly reduced in CH3CN solution. Complexes 4-6 are efficient catalysts (in 5 mol % amounts) for the aziridination of styrene with the iodinane PhINTs (in 80-90% yields vs PhINTs), while only 4 exhibits significant catalytic nitrene transfer reactivity with 1-hexene and cyclooctene.


Meiotic epigenetic factor PRDM9 impacts sperm quality of hybrid mice.
Reduced fertility of male mouse hybrids relative to their parents, or hybrid sterility, is governed by the hybrid sterility 1 (Hst1) locus. Rescue experiments with transgenes carrying sequences within or near Hst1 manifested that Hst1 contains the gene encoding meiosis-specific histone methyltransferase PRDM9. The Prdm9 gene is responsible for partial meiotic arrest, testicular atrophy, and low sperm count in (C57BL/6J x PWD)F1 mouse hybrids. Here we report that these male hybrids suffer an additional reproductive disadvantage, decreased sperm quality, which is (i) further exacerbated by the introduction of long transgenes carrying sequences from Hst1 with incomplete Prdm9 into their genome and (ii) controlled by the Prdm9 dosage. These transgenic male hybrids displayed the features of severe oligoasthenoteratozoospermia (OAT), a human infertility syndrome characterized by a low number of spermatozoa with poor motility and morphological abnormalities. Analysis of spermiogenesis in these mice revealed acrosome detachment, aberrant elongation and condensation of the nucleus. As a result, the transgenic sperm had acrosome malformations, abnormal chromatin packaging, and fragmented DNA with elevated base oxidation, revealed by using multiple methods. Heterozygosity for one null Prdm9 allele improved meiotic progression and sperm quality of both non- and transgenic hybrids. Our results indicate that genomic analysis of OAT patients should include consideration of allelic variants in PRDM9, and our transgenic models can serve as tools to understand the diverse molecular processes that, when perturbed, can cause this disease.


Echocardiographic Analysis of Correlation Between Right Ventricle Load and Function and Left Ventricle Diastolic Malfunction in Symptomless Valvular Cardiovascular Disease Patients.
BACKGROUND Left ventricle diastolic malfunction (LVDMf) is a valvular cardiovascular disease. Here, we assessed the correlation between right ventricle (RV) load and function (L&F) and diastolic malfunction (DMf) in symptomless valvular cardiovascular disease patients. MATERIAL AND METHODS We enrolled 59 subjects who underwent right-heart catheterization, assessing their echocardiographic analysis results while performing exercises in supine position, comparing results at rest and during maximum exercise. Subjects were furthermore stratified according to resting DMf. Using cardiac resonance imaging (CRM), we assessed cardiac morphology and chamber size. RV stroke, pulmonary artery conformation, pulmonary artery elastance, pulmonary artery pulsatility, and right atrial (pRA) pressure were indexed for supine exercises. RESULTS We observed that DMf grade 1 (G-1) and grade 2 (G-2) were present in 28 patients and 16 patients, respectively, while the remaining 15 patients had a normal filling pattern in the left ventricle. In comparison to patients with DMf of G-1, patients with normal diastolic filling pattern had higher volume index for RV end-diastolic (endD) (81±14 mL/m² vs. 68±12 mL/m², P=0.08) and for RV end-systolic (endS) (34±11 mL/m² vs. 27±8 mL/m², P=0.07). We also observed that in G-2 DMf pulmonary artery, pressure and elastance of the pulmonary artery were enhanced and were correlated with optimum oxygen intake and RV volume (r=-0.69, P<0.001). CONCLUSIONS We found that enhancement in RV afterload, which returns to normal at rest, is correlated with mild DMf. Additionally, despite maximum exercise, it is reciprocally associated with maximum oxygen intake and right atrial pressure.


Time to get rid of the 'Modular' in neuropsychology: a unified theory of anosognosia as aberrant predictive coding.
Cognitive neuroscience, being more inclusive and ambitious in scope than cognitive neuropsychology, seems to have taken the place of the latter within the modern neurosciences. Nevertheless, recent advances in the neurosciences afford neuropsychology with epistemic possibilities that simply did not exist even 15 years ago. Human lesion studies still have an important role to play in shaping such possibilities, particularly when combined with other methods of enquiry. I first outline theoretical and methodological advances within the neurosciences that can inform and shape the rebirth of a dynamic, non-modular neuropsychology. I then use an influential computational theory of brain function, the free energy principle, to suggest an unified account of anosognosia for hemiplegia as a research example of the potential for transition from a modular, cognitive neuropsychology to a dynamic, computational and even restorative neuropsychology. These and many other adjectives that can flexibly, take the place of 'cognitive' next to 'neuropsychology' will hopefully designate the much needed rebirth and demarcation of a field, neuropsychology itself, that has somehow lost its place within the modern neurosciences and yet seems to have a unique and important role to play in the future understanding of the brain.


Cerebral metabolic profile, selective neuron loss, and survival of acute and chronic hyperglycemic rats following cardiac arrest and resuscitation.
Cortical metabolites and regional cerebral intracellular pH (pHi) were measured in normoglycemic (NM), acute hyperglycemic (AH), and chronic hyperglycemic (CH, 2 week duration, streptozotocin-induced) Wistar rat brains during cardiac arrest and resuscitation. During total ischemia in AH and CH rats (plasma glucose approximately 30 mM), cortical ATP, PCr, glucose, and glycogen all fell significantly as expected. Lactate levels increased dramatically in association with a concomitant intracellular acidosis. Although lactate reached higher concentrations in AH and CH than NM, pHi was significantly lower only in the AH group. With 5 min of reperfusion, all groups recovered to near baseline in all variables, though lactate remained elevated. In a separate aspect of the study, animals from each experimental group were allowed to recover for 4 days following resuscitation, with outcome being gauged by mortality rate and hippocampal CA1 neuron counts. NM survival rate was significantly better than AH and CH. In particular, no CH rats survived for 4 days despite rapid initial recovery. After 4 days, the AH group had suffered significantly greater CA1 neuron loss than the NM rats. In summary, our research identified differences in intra-ischemic acid-base status in the two hyperglycemic groups, suggesting that chronic hyperglycemia may alter the brain's buffering capacity. These observations may account for differences between acutely and chronically hyperglycemic subjects regarding outcome, and they suggest that factors other than hydrogen ion production during ischemia are responsible for modulating outcome.


Acute uncomplicated diverticulitis managed without antibiotics - difficult to introduce a new treatment protocol but few complications.
Routine antibiotic treatment of acute uncomplicated diverticulitis (AUD) has been shown ineffective. In this study, the adherence to a new treatment protocol for uncomplicated diverticulitis was evaluated and the incidence of complications in patients treated with and without antibiotics was investigated. A retrospective study of in-patients diagnosed with AUD at Helsingborg Hospital, Sweden between 01 January 2013 and 06 January 2015 was performed. Antibiotics were routinely administrated until 01 May 2014. Thereafter, a new antibiotic-free treatment protocol for uncomplicated diverticulitis was introduced. All the patients were followed regarding complications for minimum one year. A total of 50 patients were studied after the new protocol implementation and, 60% (n = 31) of the patients were treated without antibiotics. Specialists initiated antibiotic therapy significantly more often than registrars (p=.03). More patients in the antibiotic group had comorbidities (p=.03), apart from that, no significant differences in baseline characteristics were noted between treatment groups. Patients treated with antibiotics after introduction of the new protocol had significantly higher C-reactive protein than patients managed without antibiotics (median 117 mg/L vs. 70, p=.005). The hospital stay was shorter in the non-antibiotic group (three days vs. two days; p=.008). No significant differences in complications were observed. Protocol compliance was lower than expected, indicating that implementation of new treatment regimens is challenging. This study confirms that complications are rare in AUD treated without antibiotics. However, the selection of the sickest patients to the treatment with antibiotics limits the interpretation of the results.


How Commonly Used Inclusion and Exclusion Criteria in Antidepressant Registration Trials Affect Study Enrollment.
In clinical trials, each specific inclusion and exclusion criterion eliminates a percentage of the potentially eligible population from trial participation and thus increases the time and effort needed for enrollment in a study. Drug developers often do not have data on how these criteria affect the pool of potentially eligible subjects for their trials and, hence, they cannot factor in the impact of these criteria when designing a study and planning the time needed to complete it. Consequently, drug developers often have ambitious timelines that are unrealistic and can lead to actions that may interfere with the ability to separate the efficacy of drug versus placebo. To investigate the effects of inclusion and exclusion criteria on study enrollment, the authors quantified the effects of the inclusion and exclusion criteria commonly used in antidepressant registration trials (ARTs) by applying these criteria to the population treated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. In essence, the STAR*D study population was used as a surrogate for the general population of individuals with major depressive disorder. The effect of each criterion commonly used in ARTs was assessed in terms of the percentage of the STAR*D population that would have been excluded individually and collectively (i.e., when all criteria were applied at once). For continuous criteria such as age and severity of depression, the resulting effects have been presented graphically. Collectively, the typical inclusion and exclusion criteria used in ARTs would have eliminated at least 82% of the STAR*D population. This result means that more than 5 times the number of subjects would have to be screened to find a population that would meet the typical inclusion and exclusion criteria for an ART, directly determining the screening effort required in terms of both resources and time. Thus, developers of antidepressant drugs can use the data from this study to plan the recruitment effort required and to weigh any potential benefit of each criterion alone and in aggregate versus their cost in terms of recruitment support and time. These data also graphically illustrate for prescribers how restrictive the population likely to be enrolled in ARTs is relative to the patients whom they treat with such medications.


The effect of allogeneic presensitization on H-Y graft survival and in vitro cell-mediated responses to H-y antigen.
C57BL/6 and C57BL/10 female mice were grafted with skin from male or female donors incompatible for H-2 and/or non-H-2 antigens. Syngeneic male grafts applied after the rejection of primary allografts or syngeneic male grafts were rejected in accelerated (second set) fashion, whereas male grafts applied after primary female grafts were not. In addition, C57BL/10 female spleen cells, primed in vivo with an allogeneic (BALB/c, CBA, or B10.BR) male graft and challenged in vitro in mixed lymphocyte culture with syngeneic (C57BL/10) male cells, produced cytotoxic cells specific for syngeneic male target cells. We conclude that at least some component of H-Y is detected by female responder cells on allogeneic male cells, and that the second set cell mediated response to H-Y is not necessarily restricted by the H-2 haplotype of the primary sensitizing strain. Moreover, (CBA X B10) F1 females, primed in vivo with male cells of one parental haplotype (B10 or CBA) and challenged in vitro with male cells of the other parental haplotype (CBA or B10), fail to lyse male target cells of either parental haplotype. It therefore seems unlikely that a helper determinant shared between B10 and CBA is sufficient to explain the ability of CBA male cells to prime H-2-restricted T-cell cytotoxic responses by B10 females.


Statistical evaluation of alternative light sources for bloodstain photography.
Bloodstain photography is important in forensic applications, especially for bloodstain pattern analysis. This study compares the enhancement effect of bloodstain photography using three different types of light source: fluorescent white light, near-ultraviolet (UV) light-emitting diode (LED) light, and 410 nm LED light. Randomized complete block designs were implemented to identify the lighting that would statistically produce the best enhancement results for bloodstains on different types of surfaces. Bloodstain samples were prepared on white cotton, brown carpet, tar road, and wood. These samples were photographed in darkroom conditions using a Canon EOS 50D digital SLR camera, with Canon EFS 60 mm f/2.8 Macro USM lens. Two-way analysis of variance and Fisher's least significant difference test were used to analyze the contrast of the images. The statistical analysis showed that 410 nm light is the best among the tested lights for enhancing bloodstains on the tested surfaces, where the contrast of bloodstain to background was the highest.


Experimentally Increasing the Compliance of Titin Through RNA Binding Motif-20 (RBM20) Inhibition Improves Diastolic Function In a Mouse Model of Heart Failure With Preserved Ejection Fraction.
Left ventricular (LV) stiffening contributes to heart failure with preserved ejection fraction (HFpEF), a syndrome with no effective treatment options. Increasing the compliance of titin in the heart has become possible recently through inhibition of the splicing factor RNA binding motif-20. Here, we investigated the effects of increasing the compliance of titin in mice with diastolic dysfunction. Mice in which the RNA recognition motif (RRM) of one of the RNA binding motif-20 alleles was floxed and that expressed the MerCreMer transgene under control of the αMHC promoter (referred to as cRbm20ΔRRM mice) were used. Mice underwent transverse aortic constriction (TAC) surgery and deoxycorticosterone acetate (DOCA) pellet implantation. RRM deletion in adult mice was triggered by injecting raloxifene (cRbm20ΔRRM-raloxifene), with dimethyl sulfoxide (DMSO)-injected mice (cRbm20ΔRRM-DMSO) as the control. Diastolic function was investigated with echocardiography and pressure-volume analysis; passive stiffness was studied in LV muscle strips and isolated cardiac myocytes before and after elimination of titin-based stiffness. Treadmill exercise performance was also studied. Titin isoform expression was evaluated with agarose gels. cRbm20ΔRRM-raloxifene mice expressed large titins in the hearts, called supercompliant titin (N2BAsc), which, within 3 weeks after raloxifene injection, made up ≈45% of total titin. TAC/DOCA cRbm20ΔRRM-DMSO mice developed LV hypertrophy and a marked increase in LV chamber stiffness as shown by both pressure-volume analysis and echocardiography. LV chamber stiffness was normalized in TAC/DOCA cRbm20ΔRRM-raloxifene mice that expressed N2BAsc. Passive stiffness measurements on muscle strips isolated from the LV free wall revealed that extracellular matrix stiffness was equally increased in both groups of TAC/DOCA mice (cRbm20ΔRRM-DMSO and cRbm20ΔRRM-raloxifene). However, titin-based muscle stiffness was reduced in the mice that expressed N2BAsc (TAC/DOCAcRbm20ΔRRM-raloxifene). Exercise testing demonstrated significant improvement in exercise tolerance in TAC/DOCA mice that expressed N2BAsc. Inhibition of the RNA binding motif-20-based titin splicing system upregulates compliant titins, which improves diastolic function and exercise tolerance in the TAC/DOCA model. Titin holds promise as a therapeutic target for heart failure with preserved ejection fraction.


Successful thoracoscopic repair of traumatic diaphragmatic hernia in a child.
Traumatic diaphragmatic hernia is very rare in children, and the diagnosis is often missed or delayed. Herein, we reported a 2-year-old boy who had suffered with traumatic diaphragmatic hernia due to a car crash. The child was manifested as tachypnoea without any other severe symptoms. The computed tomography scanning showed his right diaphragm was rupture. Soon, this patient was received a thoracoscopic repair surgery, and he was discharged 2 weeks later without any complication.


International nursing student exchange: rural and remote clinical experiences in Australia.
A rural and remote international clinical exchange permits the senior nursing student to experience another culture and to develop a feel for daily life and nursing practice abroad. In a student exchange between Australia and Canada, similarities exist with regard to life and work for nurses who live in these developed countries. Similarities extend to a growing population base of original inhabitants or indigenous peoples with complex health challenges. Differences, however, are also apparent in rural and remote health care delivery due to the uniqueness of each country's demographics, nursing programs, nursing culture, and health care systems. In the rural hospitals of the Riverland region, South Australia, the Australian public and private health care systems are witnessed working side by side. Aboriginal health care with its unique cultural care practices was experienced in the remote Aboriginal community of Hermannsburg in the Northern Territory, and in the district hospital in Alice Springs. The international exchange provided the opportunity to reflect on the impact of the social determinants of health, and the similarities and differences between developed countries in nursing practice and nursing culture. The sense of community and autonomy gained in rural and remote placements in Australia provided incentive for nursing students to consider this area of practice on their return to Canada.


Optimal oral cyclosporin dosing with concomitant posaconazole post allogeneic stem cell transplantation.
Cyclosporin is an immunosuppressive agent in allogeneic hematopoietic stem cell transplantation and its metabolism is strongly affected by concomitant drugs, including posaconazole which is now extensively used as anti-fungal prophylaxis post-allograft. We undertook a retrospective audit of 29 patients undergoing their first allograft who were receiving posaconazole at the time of transition from intravenous to oral cyclosporin. This group had a median initial oral cyclosporin dose of 2.58 mg/kg bd (range 1.75-3.95) and high incidence of cyclosporin-related toxicity was noted, requiring significant dose reductions such that by day 60 the media dose was 1.60 mg/kg bd (range 0.86-3.33). We subsequently amended our dosing protocol and analyzed a further 20 patients specifying an initial oral cyclosporin dose of 2.25 mg/kg bd and found this had little impact on toxicity or requirement for dose reductions. Starting doses of no greater than 2 mg/kg bd appear optimal to prevent toxicity in allograft recipients receiving concomitant posaconazole.


Granular cell traumatic neuroma: a lesion occurring in mastectomy scars.
Granular cell changes can be observed in a variety of benign and malignant tumors, and are seen more commonly in granular cell tumors, which in about 5% of cases develop in the breast. Granular cells also have been observed in sites of previous trauma, such as surgery, and are found to be inflammatory reactions of histiocytic origin. We investigated, morphologically and immunohistochemically, 2 granular cell lesions occurring in mastectomy scars after surgery for carcinoma. Both lesions were composed of strands and nests of large granular cells, haphazardly set in a background of fibrous tissue, with sparse inflammatory infiltrates. Several tortuous hypertrophic nerve bundles were also embedded in the fibrous tissue. A few of these nerve bundles showed degenerative changes and contained granular cells. Immunohistochemically, granular cells were positive for S100 protein, neuron-specific enolase, vimentin, and CD68 antigen. We consider these proliferative lesions of peripheral nerves to have the features of both granular cell tumor and traumatic neuroma. These cases indicate that traumatic neuroma can undergo extensive granular cell changes and constitute a previously unrecognized entity, which we provisionally label granular cell traumatic neuroma. Granular cell traumatic neuroma has to be taken into consideration when evaluating lesions occurring at mastectomy scars and should be differentiated from malignant tumors with granular cells, such as apocrine carcinoma and alveolar soft part sarcoma.


The three dimensional structure of the lysozyme from bacteriophage T4.
The three dimensional structure of the lysozyme from bacteriophage T4 has been determined from a 2.5 A resolution electron density map. About 60% of the molecule is in a helical conformation and there is one region consisting of antiparallel beta-structure. The polypeptide backbone folds into two distinct lobes linked in part by a long helix. In the region between the two lobes, there is a cleft which deepens into a hole or cavity, about 6-8 A in diameter, extending from one side of the molecule to the other. This opening is closed off by side chains which extend to within 3-5 A of each other. A number of mutant lysozymes in which residues in the vicinity of the opening are modified have markedly reduced catalytic activity, suggesting that this region of the molecule may be catalytically important. The three dimensional structure of T4 phage lysozyme is quite different from that of hen egg-white lysozyme although it is not clear at this time whether or not the mechanisms of catalysis of the respective enzymes are related.


North American Contact Dermatitis Group Patch Test Results: 2017-2018.
Patch testing is an important diagnostic tool for assessment of allergic contact dermatitis (ACD). This study documented the North American Contact Dermatitis Group (NACDG) patch testing results from March 1, 2017, to December 31, 2018. At 14 centers in North America, patients with dermatitis were tested in a standardized manner with a screening series of 70 allergens and supplemental allergens as clinically indicated. Data were manually verified and entered into a central database. Descriptive statistics were estimated, and trends were analyzed using χ2 test. Overall, 4947 patients were tested. There were 3235 patients (65.4%) who had at least 1 positive reaction and 2495 patients (50.4%) had a primary diagnosis of ACD. Five hundred eighty-one patients (11.7%) had occupationally related dermatitis. There were 10,122 positive patch test reactions. Nickel remained the most commonly detected allergen (16.2%), followed by methylisothiazolinone 0.2% aqueous (15.3%) and methylchloroisothiazolinone/methylisothiazolinone 0.02% aqueous (200 ppm, 11.0%). Compared with the previous reporting periods (2015-2016 and 2007-2016), the proportion of positive reactions for the top 20 screening allergens statistically increased for only 1 allergen, propolis (3.4%; risk ratios = 2.05 [confidence interval = 1.66-2.54] and 1.82 [confidence interval = 1.57-2.11]).Four newly added allergen preparations, hydroperoxides of linalool (8.9%), benzisothiazolinone (7.3%), sodium metabisulfite (2.7%), and hydroperoxides of limonene (2.6%), all had a prevalence of greater than 2%. Approximately 1 (19.7%) in 5 tested patients had 1 or more clinically relevant reactions to an allergen not on the NACDG screening series; 13.2% of these were occupationally related. T.R.U.E. TEST (SmartPractice Denmark, Hillerød, Denmark) would have hypothetically missed 30% to 40% of reactions detected by the NACDG screening series. These results demonstrate the importance of a regularly updated screening allergen series. Methylisothiazolinone continues to be a significant allergen in North America. Patch testing with allergens beyond a screening tray is necessary for complete evaluation of occupational and non-occupational ACD.


What is the role of maintenance rituximab in follicular NHL?
Recent trials have demonstrated improvements in progression-free and overall survival with the inclusion of the chimeric anti-CD20 monoclonal antibody rituximab (Rituxan) in chemotherapy regimens for treatment-naive and relapsed patients with advanced-stage follicular non-Hodgkin's lymphoma (NHL). As rituximab therapy has significant single-agent activity infollicular NHL, is generally well tolerated, and has no dose-limiting or significant hematologic toxicity, a number of approaches evaluating maintenance therapy with extended dosing of rituximab are being tested. Trials have demonstrated prolonged progression-free survival in patients treated with maintenance rituximab using a variety of schedules following treatment with single-agent rituximab, induction or salvage chemotherapy, or salvage therapy with rituximab and chemotherapy combinations. Small increases in neutropenia and infections have been reported with extended rituximab use. Ongoing trials are evaluating the optimal use of rituximab (maintenance vs. retreatment) and the benefit of rituximab maintenance following treatment of therapy-naive patients treated with rituximab-containing chemoimmunotherapy induction regimens. This article discusses the risks and benefits of maintenance rituximab for follicular NHL.


Hyperhomocysteinemia: a missing link to dysfunctional HDL via paraoxanase-1.
Paraoxanase-1 (PON1) is an HDL-associated enzyme that contributes to the antioxidant and antiatherosclerotic properties of HDL. Lack of PON1 results in dysfunctional HDL. HHcy is a risk factor for cardiovascular disorders, and instigates vascular dysfunction and ECM remodeling. Although studies have reported HHcy during atherosclerosis, the exact mechanism is unclear. Here, we hypothesize that dysfunctional HDL due to lack of PON1 contributes to endothelial impairment and atherogenesis through HHcy-induced ECM re-modeling. To verify this hypothesis, we used C57BL6/J and PON1 knockout mice (KO) and fed them an atherogenic diet. The expression of Akt, ADMA, and DDAH, as well as endothelial gap junction proteins such as Cx-37 and Cx-40 and eNOS was measured for vascular dysfunction and inflammation. We observed that cardiac function was decreased and plasma Hcy levels were increased in PON1 KO mice fed the atherogenic diet compared with the controls. Expression of Akt, eNOS, DDAH, Cx-37, and Cx-40 was decreased, and the expression of MMP-9 and ADMA was increased in PON1 KO mice fed an atherogenic diet compared with the controls. Our results suggest that HHcy plays an intricate role in dysfunctional HDL, owing to the lack of PON1. This contributes to vascular endothelial impairment and atherosclerosis through MMP-9-induced vascular remodeling.


Transformation-deficient mutants of Bacillus subtilis impaired in competence-specific nuclease activities.
A comparison of the nucleolytic activities in competent and physiologically low-competent wild-type cultures of Bacillus subtilis in DNA-containing sodium dodecyl sulfate-polyacrylamide gels revealed the existence of three competence-associated nuclease activities with apparent molecular weights of 13,000, 15,000, and 26,000. The three activities, which were dependent on manganese or magnesium ions, were specifically present in the competent fraction of a competent culture. The competence-associated nucleolytic activities of eight transformation-defective mutant strains were assayed, resulting in the following three classes of mutants: (i) four strains which, according to this assay, were not impaired in any of the nucleolytic activities mentioned above; (ii) one strain which was strongly impaired in the 13,000- and 26,000-molecular-weight activities, but showed a considerable level of the 15,000-molecular-weight activity; and (iii) three strains which were severely impaired in all three activities. The results indicated that the 26,000-molecular-weight activity was a dimer of the 13,000-molecular-weight activity and that this nuclease was involved in the entry of DNA.


Mutants deleted in the agnogene of simian virus 40 define a new complementation group.
Analysis of the DNA sequence of the late leader region of simian virus 40 indicates that it might encode a 61-amino acid, highly basic protein, LP-1. Mutants deleted in this region are viable, but they produce infectious progeny more slowly than wild-type virus in established monkey cells. On the basis of the rates of appearance and the sizes of mixed plaques formed after cotransfections with pairs of mutants, we found that mutants defective in the synthesis of LP-1 complementation was also observed in infections with virions and was bidirectional. Therefore, these mutants define a new complementation group, group G. In addition, a protein of the appropriate molecular weight for LP-1 (approximately 8 X 10(3) ) was synthesized by wild-type virus-infected cells but not by mock-infected or group G gene mutant-infected cells. This protein, whose identity has been established definitively by Jay et al. (Nature (London) 291:346-349, 1981), was synthesized at a high rate at late times after infection, was present predominantly in the cytoplasmic fraction of cells, possessed a fairly short half-life, and was absent from mature virions. Once formed, virions of group G gene mutants behaved biologically and physically like virions of wild-type virus. On the basis of these findings and other known properties of LP-1 and mutants defective in LP-1 synthesis, we hypothesize that LP-1 functions to facilitate virion assembly, possibly by serving as a nonreusable scaffolding protein.


A roadmap for social determinants of health and biological nursing research in the National Institute of Nursing Research 2022-2026 Strategic Plan: Optimizing health and advancing health equity using antiracist framing.
Health equity is essential for improving the well-being of all individuals and groups, and research remains a critical element for understanding barriers to health equity. While considering how to best support research that acknowledges current health challenges, it is crucial to understand the role of social justice frameworks within health equity research and the contributions of minoritized researchers. Additionally, there should be an increased understanding of the influence of social determinants of health on biological mechanisms. Biological health equity research seeks to understand and address health disparities among historically excluded populations. While there are examples of studies in this area led by minoritized researchers, some individuals and groups remain understudied due to underfunding. Research within minoritized populations must be prioritized to authentically achieve health equity. Furthermore, there should be increased funding from National Institutes of Health to support minoritized researchers working in this area.


Prediction of individual life-years gained without cardiovascular events from lipid, blood pressure, glucose, and aspirin treatment based on data of more than 500 000 patients with Type 2 diabetes mellitus.
Although group-level effectiveness of lipid, blood pressure, glucose, and aspirin treatment for prevention of cardiovascular disease (CVD) has been proven by trials, important differences in absolute effectiveness exist between individuals. We aim to develop and validate a prediction tool for individualizing lifelong CVD prevention in people with Type 2 diabetes mellitus (T2DM) predicting life-years gained without myocardial infarction or stroke. We developed and validated the Diabetes Lifetime-perspective prediction (DIAL) model, consisting of two complementary competing risk adjusted Cox proportional hazards functions using data from people with T2DM registered in the Swedish National Diabetes Registry (n = 389 366). Competing outcomes were (i) CVD events (vascular mortality, myocardial infarction, or stroke) and (ii) non-vascular mortality. Predictors were age, sex, smoking, systolic blood pressure, body mass index, haemoglobin A1c, estimated glomerular filtration rate, non- high-density lipoprotein cholesterol, albuminuria, T2DM duration, insulin treatment, and history of CVD. External validation was performed using data from the ADVANCE, ACCORD, ASCOT and ALLHAT-LLT-trials, the SMART and EPIC-NL cohorts, and the Scottish diabetes register (total n = 197 785). Predicted and observed CVD-free survival showed good agreement in all validation sets. C-statistics for prediction of CVD were 0.83 (95% confidence interval: 0.83-0.84) and 0.64-0.65 for internal and external validation, respectively. We provide an interactive calculator at www.U-Prevent.com that combines model predictions with relative treatment effects from trials to predict individual benefit from preventive treatment. Cardiovascular disease-free life expectancy and effects of lifelong prevention in terms of CVD-free life-years gained can be estimated for people with T2DM using readily available clinical characteristics. Predictions of individual-level treatment effects facilitate translation of trial results to individual patients.


Innate immune response after resuscitation with hemoglobin-based oxygen carrier and recombinant factor VIIA in uncontrolled hemorrhagic shock in a swine model.
Rapid resuscitation with oxygen-carrying fluids is critically important in hemorrhagic shock (HS) combat casualties in remote areas where blood is not available. Hemoglobin-based oxygen carrier-201 (HBOC-201) has been shown to increase survival and reduce immune activation following HS in animal models. Recombinant factor VIIa (rfVIIa), a systemic hemostatic agent, is Food and Drug Administration approved for use in acute hemorrhage in hemophilic patients. The combination of HBOC-201 and rfVIIa may form the basis of a prospective multifunctional blood substitute and provide benefits in the rapid restoration of hemostasis, decreased inflammation and improved survival of HS combat casualties. In the present study, we evaluated innate immune responses in a swine model of uncontrolled HS following resuscitation with HBOC-201 +/- rfVIIa. Thirty-two pigs underwent uncontrolled hemorrhage/liver crush injury, followed by resuscitation with five doses of HBOC-201 or HBOC + rfVIIa (90 microg/kg, or 180 microg/kg, or 360 microg/kg) and simulated 4 hours hospital arrival. Immune parameters were evaluated by flow cytometry and enzyme-linked immunosorbent assay. Survival differences to 72 hours of animals resuscitated with HBOC, HBOC + rfVIIa (90), (180), and (360) were not statistically significant and resulted in survival of 25%, 63%, 63% and 50%, respectively. At the prehospital phase all groups exhibited minimal immunomodulation, characterized by stable CD4/CD8 ratio, marginal increase of apoptosis and insignificant fluctuations of adhesion markers; increase of plasma cytokines was comparable across all groups, except tumor necrosis factor-alpha, that was significantly elevated in the HBOC group. HBOC-201 + rfVIIa triggered minimum immune activation in an uncontrolled HS swine and there was a nonsignificant survival benefit.


Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia.
During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P2. Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart.


Ginsenoside Rb2 Alleviates Hepatic Lipid Accumulation by Restoring Autophagy via Induction of Sirt1 and Activation of AMPK.
Although Panax ginseng is a famous traditional Chinese medicine and has been widely used to treat a variety of metabolic diseases including hyperglycemia, hyperlipidemia, and hepatosteatosis, the effective mediators and molecular mechanisms remain largely unknown. In this study we found that ginsenoside Rb2, one of the major ginsenosides in Panax ginseng, was able to prevent hepatic lipid accumulation through autophagy induction both in vivo and in vitro. Treatment of male db/db mice with Rb2 significantly improved glucose tolerance, decreased hepatic lipid accumulation, and restored hepatic autophagy. In vitro, Rb2 (50 µmol/L) obviously increased autophagic flux in HepG2 cells and primary mouse hepatocytes, and consequently reduced the lipid accumulation induced by oleic acid in combination with high glucose. Western blotting analysis showed that Rb2 partly reversed the high fatty acid in combination with high glucose (OA)-induced repression of autophagic pathways including AMP-activated protein kinase (AMPK) and silent information regulator 1 (sirt1). Furthermore, pharmacological inhibition of the sirt1 or AMPK pathways attenuated these beneficial effects of Rb2 on hepatic autophagy and lipid accumulation. Taken together, these results suggested that Rb2 alleviated hepatic lipid accumulation by restoring autophagy via the induction of sirt1 and activation of AMPK, and resulted in improved nonalcoholic fatty liver disease (NAFLD) and glucose tolerance.


Strategies in frozen donor semen procreation.
Data were analysed from 710 couples who had been assessed to determine the effectiveness and the drawbacks of three different methods of insemination using frozen donor semen. Intracervical insemination (ICI) was the first method used when the women had no tubal disorder: 255 pregnancies were achieved in a total of 2558 cycles (10%). Intrauterine insemination (IUI) associated with ovarian stimulation resulted in 152 pregnancies over 966 cycles (16%). In-vitro fertilization (IVF) was proposed after approximately 12 insemination failures using either of the other methods or when the initial gynaecological examination had revealed abnormalities such as tubal occlusions; 48 pregnancies were obtained in 262 cycles (18.3%). The pregnancy rate using ICI was significantly higher when two inseminations were performed per cycle, compared with one insemination per cycle (12.3 versus 7%, P < 0.001). The number of motile spermatozoa per straw was correlated with the pregnancy rate when using ICI, rising from 9% with < 4 x 10(6) motile spermatozoa to 13.8% with 4-8 x 10(6) and 17.2% with > 8 x 10(6). No relationship was found between the number of motile spermatozoa and the pregnancy rate using IUI and IVF. The incidence of primary ovulatory disorder was higher among women whose husbands were oligozoospermic than among those whose husbands were azoospermic (19 versus 9%, P < 0.01), but ovarian stimulation improved the fecundity of subfertile women. The outcome of pregnancies was also analysed for the three methods. From these data, strategic plans have been proposed to maximize the pregnancy rate for women undergoing therapeutic donor insemination with frozen semen.


The developmental program of fast myosin heavy chain expression in avian skeletal muscles.
We have examined the types of fast myosin heavy chains (MHCs) expressed in a number of different developing chicken skeletal muscles by combining peptide mapping and immunoblotting to identify fast MHC-specific peptides among the total mixture of MHC digestion products. Using this technique, we have identified three different fast MHC patterns among the different fast and mixed (i.e., fast and slow) fiber type muscles of the adult. While the different muscles all underwent sequential changes in fast MHC isoform expression during their development, the exact sequence of these changes and the isoform patterns expressed varied from muscle to muscle. During late embryonic or fetal development, all muscles expressed a similar fast MHC pattern (designated here as the fetal pattern) which was replaced shortly after hatching with a different fast MHC pattern (the neonatal pattern). During the transition from the neonatal to the adult state that occurred sometime in the first year after hatching, many of the muscles underwent additional changes in fast MHC isoform expression. In muscles such as the pectoralis major and pectoralis minor, a new fast MHC isoform pattern was seen in the adult so that the developmental program of isoform switching in these muscles involved the sequential appearance of distinct fetal, neonatal, and adult fast MHCs. Other muscles, such as the sartorius and posterior latissimus dorsi, underwent a qualitatively different program of isoform switching and expressed as an adult a fast MHC pattern that was indistinguishable from that expressed during fetal development. Finally, in some muscles, such as the superficial biceps, no change in isoform pattern was detected during the neonatal to adult transition--in these muscles, expression of the neonatal MHC isoform pattern apparently persisted into the adult state. These data indicate that no single scheme or program of fast MHC isoform switching can describe all the developmental changes that occur in fast MHC isoform expression in the chicken and that at least three different programs of isoform switching and expression can be identified.


Polysulfide Catalytic Materials for Fast-Kinetic Metal-Sulfur Batteries: Principles and Active Centers.
Benefiting from the merits of low cost, ultrahigh-energy densities, and environmentally friendliness, metal-sulfur batteries (M-S batteries) have drawn massive attention recently. However, their practical utilization is impeded by the shuttle effect and slow redox process of polysulfide. To solve these problems, enormous creative approaches have been employed to engineer new electrocatalytic materials to relieve the shuttle effect and promote the catalytic kinetics of polysulfides. In this review, recent advances on designing principles and active centers for polysulfide catalytic materials are systematically summarized. At first, the currently reported chemistries and mechanisms for the catalytic conversion of polysulfides are presented in detail. Subsequently, the rational design of polysulfide catalytic materials from catalytic polymers and frameworks to active sites loaded carbons for polysulfide catalysis to accelerate the reaction kinetics is comprehensively discussed. Current breakthroughs are highlighted and directions to guide future primary challenges, perspectives, and innovations are identified. Computational methods serve an ever-increasing part in pushing forward the active center design. In summary, a cutting-edge understanding to engineer different polysulfide catalysts is provided, and both experimental and theoretical guidance for optimizing future M-S batteries and many related battery systems are offered.


One-dimensionality of phonon transport in cup-stacked carbon nanofibers.
We treat the ballistic heat conduction of cup-stacked carbon nanofibers (CSCNF) by a nonequilibrium molecular dynamics simulation. The CSCNF consist of numerous tiny graphene cups linked in line by weak intermolecular forces. The simulation results show that the thermal conductivity varies with the fiber length in a power law fashion with an exponent as large as 0.7. The calculated phonon density of states revealed that a low frequency oscillation in the radial and axial directions dominates the heat conduction in CSCNF. The atomic motions indicate that these low frequency oscillations are quasi-one-dimensional (1D) where each cup moves axially like a rigid body and radially with a breathing motion. This quasi-1D oscillation occurs due to the unique structure of a CSCNF that resembles a 1D harmonic chain. Our investigations show that treating a CSCNF as a 1D chain with three-dimensional oscillations explains why this material has the highest ballistic phonon transport ever observed.


Influence of temperature on diffractive lens performance.
The thermal properties of lenses play an important role in the performance of optical systems. We discuss the effects of uniform temperature changes and thermal gradients on diffractive lens performance. Comparisons are made between the thermal sensitivity of refractive and diffractive lenses. Useful design equations are presented that describe focal length, phase coefficients, and diffraction efficiency as functions of temperature. We present important thermal data for a number of lens materials. The optothermal expansion coefficient is used to design athermalized lenses that combine refractive and diffractive surfaces.


Blood product recalls in the United States.
The blood recall process is intended to remove from use products that may be harmful, but characteristics of recalls nationally have not been reported. We analyzed recalls of all blood products for 2010 and categorized the reason for the recall, the organizations producing the recalled products, and the Food and Drug Administration (FDA) district in which the blood was collected. During 2010, there were 2468 recalls involving 8278 blood products. None of the recalls was considered to have a reasonable probability of causing serious adverse health consequences or death (FDA Class I). The most common reasons for recalls were donation and donor qualification (73%) and finished product quality control (14%). The FDA class of recalls varied by recall reason, month of the year, FDA district, number of units of blood collected per FDA district, and number of units of blood collected by the blood center. The number of recalls per 100,000 units of blood and the reason for recall varied by FDA district and blood centers collecting smaller numbers of units had more recalls. The absence of Class I recalls suggests a high level of quality and safety in the US blood supply. Organizations that collected larger numbers of units of blood had fewer recalls and there may be some FDA influences since the number and reason for the recalls varied by FDA district.


Challenges in identifying antibiotic resistance targets for point-of-care diagnostics in general practice.
General practitioners stand at the front line of healthcare provision and have a pivotal role in the fight against increasing antibiotic resistance. In this respect, targeted antibiotic prescribing by general practitioners would help reduce the unnecessary use of antibiotics, leading to reduced treatment failures, fewer side-effects for patients and a reduction in the (global) spread of antibiotic resistances. Current 'gold standard' antibiotic resistance detection strategies tend to be slow, taking up to 48 h to obtain a result, although the implementation of point-of-care testing by general practitioners could help achieve the goal of targeted antibiotic prescribing practices. However, deciding on which antibiotic resistances to include in a point-of-care diagnostic is not a trivial task, as outlined in this publication.


Fatigue in phasic and tonic fibers of frog muscle.
Single isolated phasic muscle fibers and small bundles of tonic fibers were directly stimulated in one-per-second twitch series by massive electrode shocks. During the stimulation period the isometric tension developed by the phasic fiber continuously decreased, first rapidly and then slowly. The tonic fibers behaved similarly, but showed much less fatigue than the phasic ones. In general, recovery of the fibers after cessation of stimulation also occurred in two phases.


In vivo wound healing activity and phytochemical screening of the crude extract and various fractions of Kalanchoe petitiana A. Rich (Crassulaceae) leaves in mice.
The leaves of Kalanchoe petitiana A. Rich (Crassulaceae) are used in Ethiopian folk medicine for treatment of evil eye, fractured surface for bone setting and several skin disorders including for the treatment of sores, boils, and malignant wounds. In order to scientifically prove the claimed utilization of the plant, the effects of the extracts and the fractions were investigated using in vivo excision, incision and dead space wound models. Mice were used for wound healing study, while rats and rabbit were used for skin irritation test. For studying healing activity 80% methanolic extract and the fractions were formulated in strength of 5% and 10%, either as ointment (hydroalcoholic extract, aqueous and methanol fractions) or gel (chloroform fraction). Oral administration of the crude extract was used for dead space model. Negative controls were treated either with simple ointment or sodium carboxyl methyl cellulose xerogel, while positive controls with nitrofurazone (0.2 w/v) skin ointment. Negative controls for dead space model were treated with 1% carboxy methyl cellulose. Parameters, including rate of wound contraction, period of complete epithelializtion, hydroxyproline contents and skin breaking strength were evaluated. Significant wound healing activity was observed with ointment formulated from the crude extract at both 5% and 10% concentration (p<0.01) compared to controls in both excision and incision models. In dead space model, 600 mg/kg (p<0.01) but not 300 mg/kg significantly increased hydroxyproline content. Fractions showed variable effect, with the chloroform fraction lacking any significant effect. Both 5% and 10% formulations of the aqueous and methanolic fractions significantly increased wound contraction, decreased epithelializtion time and increased hydroxyproline content in excision wound model (p<0.05) as compared to controls. These fractions were also endowed with higher skin breaking strength in incision wound model (p<0.01). The present study provided evidence that the leaves of Kalanchoe petitiana A. Rich possess remarkable wound healing activities supporting the folkloric assertion of the plant. Fractionation revealed that polar or semi polar compound may play vital role, as both aqueous and methanolic fractions were endowed with wound healing activity.