Management of supraventricular tachycardia using the Valsalva manoeuvre: a historical review and summary of published evidence.
Use of the Valsalva manoeuvre (VM) as a first-line management tool for the reversion of supraventricular tachycardia (SVT) in both emergency medicine and prehospital emergency-care settings has presented challenges, requiring continuous examination and refinement to define both its appropriateness and effectiveness. This report details the evolution of knowledge related to SVT and the historical evolution and controversies associated with VM; it also highlights the ongoing development of an evidence-based model of practice for the management of SVT in the emergency medicine and prehospital emergency-care settings. A two-part review of the literature using electronic medical databases was conducted. Other relevant texts or articles unavailable within the electronic search were also identified. Part 1 of the search criteria identified the historical evolution of the pathophysiology of SVT, whereas part 2 identified the use of VM for the clinical management of SVT. Part 1 of the review identified a total of 38 articles with eight meeting the inclusion criteria, and part 2 of the review identified a total of 44 articles with 17 meeting the inclusion criteria. An evidence-based model of practice requires clarification. The differentiation of nodal re-entrant tachycardias may, with further research, lead to identification of the specificity of VM in reversion of SVT during the early stages of arrhythmia. There is a need for further prehospital and emergency department research to quantify an evidence-based approach to VM.


Music Does Not Facilitate Lexical Tone Normalization: A Speech-Specific Perceptual Process.
Listeners utilize the immediate contexts to efficiently normalize variable vocal streams into standard phonology units. However, researchers debated whether non-speech contexts can also serve as valid clues for speech normalization. Supporters of the two sides proposed a general-auditory hypothesis and a speech-specific hypothesis to explain the underlying mechanisms. A possible confounding factor of this inconsistency is the listeners' perceptual familiarity of the contexts, as the non-speech contexts were perceptually unfamiliar to listeners. In this study, we examined this confounding factor by recruiting a group of native Cantonese speakers with sufficient musical training experience and a control group with minimal musical training. Participants performed lexical tone judgment tasks in three contextual conditions, i.e., speech, non-speech, and music context conditions. Both groups were familiar with the speech context and not familiar with the non-speech context. The musician group was more familiar with the music context than the non-musician group. The results evidenced the lexical tone normalization process in speech context but not non-speech nor music contexts. More importantly, musicians did not outperform non-musicians on any contextual conditions even if the musicians were experienced at pitch perception, indicating that there is no noticeable transfer in pitch perception from the music domain to the linguistic domain for tonal language speakers. The findings showed that even high familiarity with a non-linguistic context cannot elicit an effective lexical tone normalization process, supporting the speech-specific basis of the perceptual normalization process.


[Diagnostic strategies in Hepatitis C virus infection].
Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis. The World Health Organization estimates that 170 million people world-wide are infected with HCV; 70% of them will develop chronic hepatitis and 20-30% cirrhosis in 10-30 years. Of those with cirrhosis, an estimated 25-30% will develop liver cancer. Since the identification and molecular characterization of HCV in 1989, a variety of diagnostic tests based on the detection of hepatitis virus antibodies or HCV RNA in the serum have been developed. The enzyme-linked immunosorbent assays (ELISA 3) and the recombinant immunoblot assays (RIBA 2nd and 3rd generation) exhibit improved sensitivity and specificity for HCV antibodies. Qualitative and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) has allowed clinicians to track the natural history of HCV and to monitor the progress of therapy. This article reviews the state-of-the-art tests and assays developed for the diagnosis and management of HCV infection.


Evidence from fatal COVID-19 for targeting the bradykinin metabolism - a single-center cohort study.
Severe progression of COVID-19 to critical illness, with pulmonary failure, multiple organ failure, and death, is driven by systemic inflammatory responses with overproduction of inflammatory cytokines. In the past years, the potential role of bradykinin, leading to inappropriate immune responses in the pathogenesis of COVID-19, has been raised in a so-called "bradykinin-storm". However, clinical investigations of bradykinin, its metabolite des-Arg9-bradykinin, or substance P, are rare or completely lacking during intensive care of COVID-19 patients.A prospective prolonged cohort study was conducted, including 44 COVID-19 patients (09/2020 - 02/2021; prevalent wildtype SARS CoV-2) from the intensive care unit. Plasma levels of bradykinin, des-Arg9-bradykinin, and substance P were measured daily by ELISA in survivors (n = 21) and non-survivors (n = 23) of COVID-19 from admission until discharge or death. We found significantly higher plasma levels of des-Arg9-bradykinin in survivors and non-survivors of COVID-19 compared to healthy controls. In addition, plasma des-Arg9-bradykinin levels were higher (p < 0.001; effect size = 0.79) in non-survivors compared to survivors of COVID-19, and correlated significantly with disease worsening, and clinical parameters of inflammation, like leukocyte count, IL-6 or LDH, and outcome. Consequently, compared to healthy controls, bradykinin and substance P plasma levels were significantly reduced in survivors and non-survivors of COVID-19. Furthermore, plasma substance P levels were significantly reduced (p < 0.001; effect size = 0.7) in non-survivors compared to survivors of COVID-19, whereas plasma bradykinin levels did not significantly differ between survivors and non-survivors of COVID-19. In conclusion, our data demonstrates that des-Arg9-bradykinin is significantly elevated in COVID-19 ICU patients and is associated with disease severity, clinical inflammatory parameters, and survival. These results indicate that des-Arg9-bradykinin, not bradykinin, is one of the pivotal peptides of concern for the lethal COVID-19 aggravation and outcome. Further investigations are necessary to evaluate whether des-Arg9-bradykinin exhibits potent blood biomarker properties in COVID-19 and offer new treatment approaches.


Comparison of Propofol-Fentanyl with Midazolam-Ketamine Combination in Pediatric Patients Undergoing Kidney Biopsy.
Kidney biopsy is a procedure of choice for the diagnosis of many kidney diseases. In children it is performed with the use of sedatives. The aim of this study was to compare the combination of propofol/fentanyl with midazolam/ketamine for sedation in pediatric patients undergoing kidney biopsy. In this double-blinded clinical trial, seventeen children, candidate of kidney biopsy were included and randomized into two groups. One group received Midazolam/Ketamine with doses of 30 to 50 μg/kg and 0.25 to 1 mg/kg, and the other group were sedated with propofol/fentanyl combination in doses of 0.5 to 1 mg/kg and 0.5 to 1 mg/kg, respectively. Administration time, medication doses, total procedure time, need for analgesic use after the procedure, and patient relaxation, with no agitation during and after the biopsy were recorded. Nine patients received midazolam/ketamine and eight received propofol/fentanyl. None of them experienced vomiting or itching after sedation. There were no meaningful differences in qualitative variables of the need for pain relief between two groups. Regarding the distribution of pain at the time of sedation, and 1, 3, 6, and 24 hours after sedation, there was no significant statistical difference between the two groups. There was also no significant statistical difference between the two groups, regarding patients' relaxation during, and 1, 3, 6, and 24 hours after biopsy. There was no statistically significant difference between the degree of sedation and the analgesic effect of the two regimens in the two groups. DOI: 10.52547/ijkd.6982.


Binding of two novel bisdaunorubicins to DNA studied by NMR spectroscopy.
In the search for new generations of anthracycline drugs, lower cytotoxic side effects and higher activity against resistant cancer cells are two major goals. A new class of bis-intercalating anthracycline drugs has been designed, synthesized, and shown to have promising activity against multidrug-resistant cells. Two daunorubicins symmetrically linked together via a p-xylenyl group, either at their N3' (compound WP631) or N4' sites (compound WP652), exhibit extraordinary DNA binding affinities. We have used high-resolution NRM studies to understand the DNA binding mode of these two new bis-daunorubicin anticancer compounds. The structures of the WP631-d(ACGTACGT)2 and the WP652-d(TGTACA)2 complexes have been determined by NOE-restrained refinement. WP631 binds strongly to the 5'-CG(A/T)(A/T)CG hexanucleotide sequence, with the aglycons intercalated between the two CpG sites at both ends of the hexanucleotide sequence. The overall conformation of the WP631-d(CGTACG)2 part is remarkably similar to the crystal structure of the 2:1 complex of daunorubicin and d(CGTACG)2, as predicted previously [Gao, Y.-G., & Wang, A.H.H. (1996), J. Biomol. Struct. Dyn. 13, 103-117]. In contrast, the related bis-intercalator WP652 prefers the 5'-PyGTPu tetranucleotide sequence, with the aglycons intercalated between the PypG and TpPu sites. The binding of WP652 to DNA results in a severely distroted B-DNA duplex with the p-xylenyl tether moiety significantly protruded away from the bottom of the minor groove. While WP652 in some ways behaves similarly to other anticancer bis-intercalating antibiotics (e.g., triostine A and echinomycin), the detailed interactions between those two classes of bis-intercalators are quite different.


Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis.
Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab. To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS. This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country. Treatment with ocrelizumab or rituximab after 2015. Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups. Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses. In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials.


[Hospital centers of proton radiotherapy--problems and possible solutions].
Principles and scope of application of proton therapy in hospitals are discussed. Main distinctions between the dose distribution of megavolt gamma radiation and that of proton radiation are due to that the latter is totally absent behind the target and energy gradients along the lateral and back site boundaries of the proton irradiation field are high. Data on the operating proton therapy centers and those being designed are presented. The unjustifiably slow rate of integration of the proton technique with clinical practice is due to the time-consuming nature of relevant research. Possible ways and means of obviating the difficulties involved are discussed.


Do alternate bacterial indicators and pathogens increase after centrifuge dewatering of anaerobically digested biosolids?
The objectives of this research were to evaluate the potential for sudden increase and/or regrowth of alternative bacteria as either indicators or pathogens after dewatering of thermophilic and mesophilically digested biosolids. The results showed that, in general, for thermophilic processes, even when a statistically significant (p < 0.05) sudden increase and regrowth occurred for fecal coliforms, Escherichia coli, and Enterococci, it did not occur for Salmonella or Aeromonas. For the mesophilic process evaluated, sudden increase did not occur, but regrowth occurred for fecal coliforms, E. coli, Enterococci, and Salmonella. The results have implications for Class A and B biosolids regulations, as both fecal coliform and Salmonella are part of the regulatory limits. The results also suggest that the public health risks are minimal, as a result of the potential sudden increase and regrowth that may occur.


Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease.
Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B-cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multiorgan system, nonsclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells, but not T cells, for disease progression. Bone marrow-specific Syk deletion in vivo was effective in treating established cGVHD, as was a small-molecule inhibitor of Syk, fostamatinib, which normalized GC formation and decreased activated CD80/86(+) dendritic cells. In multiple distinct models of sclerodermatous cGVHD, clinical and pathological disease manifestations were not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these scleroderma models. We further demonstrated that Syk inhibition was effective at inducing apoptosis of human cGVHD B cells. Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD.


Reduced supplementation frequency increased insulin-like growth factor 1 in beef steers fed medium quality hay and supplemented with a soybean hull and corn gluten feed blend.
Reducing supplementation frequency in calf growing programs can reduce labor and equipment operation costs. However, little is understood about the metabolic response of ruminants to large fluctuations in nutrient intake. Eighteen Angus or Angus × Simmental cross steers (287 ± 20 kg and 310 ± 3.6 d of age) were individually fed 1 of 3 dietary treatments using Calan gates. Dietary treatments consisted of ad libitum hay and no supplement (NS), ad libitum hay and 1% BW (as-fed basis) of supplement daily (DS), or ad libitum hay and 2% BW (as-fed basis) of supplement every other day (SA). The supplement was 90% DM and contained (as-fed basis) 47% corn gluten feed, 47% soybean hulls, 2% feed grade limestone, and 4% molasses. Hay intake and ADG was measured over a 52-d period. Steers were then moved to individual tie stalls. Steers were fed at 0800 h and blood samples were collected every hour from 0600 to 1400 h and at 1800, 2200, and 0200 h over a 2-d period. Gains were increased (P < 0.01) by supplementation but did not differ (P = 0.68) due to supplementation frequency. Average daily gain was 0.45, 0.90, and 0.87 kg ·hd(-1)·d(-1) (SEM ± 0.05) for steers NS, DS, and SA, respectively. Across the 2-d supplementation cycle area under the concentration time curve (AUC) for plasma glucose was increased (P < 0.01) by supplementation but did not differ (P = 0.41) due to supplementation frequency. The AUC for plasma insulin was increased by supplementation (P < 0.01) but did not differ (P = 0.67) due to supplementation frequency. Plasma IGF-1 was increased (P = 0.01) by supplementation and was greater (P = 0.04) for steers supplemented SA than DS. Gains of steers supplemented with a soybean hull and corn gluten feed blend on alternate days did not differ from those supplemented daily suggesting the steers were able to efficiently utilize large boluses of nutrients fed every other day. The effect of less frequent supplementation on IGF-1 deserves further examination as this hormone has been shown to increase protein synthesis.


Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis.
Steroid receptors in the stromal cells of endometrium and its disease counterpart tissue endometriosis play critical physiologic roles. We found that mRNA and protein levels of estrogen receptor 2 (ESR2) were strikingly higher, whereas levels of estrogen receptor 1 (ESR1), total progesterone receptor (PGR), and progesterone receptor B (PGR B) were significantly lower in endometriotic versus endometrial stromal cells. Because ESR2 displayed the most striking levels of differential expression between endometriotic and endometrial cells, and the mechanisms for this difference are unknown, we tested the hypothesis that alteration in DNA methylation is a mechanism responsible for severely increased ESR2 mRNA levels in endometriotic cells. We identified a CpG island occupying the promoter region (-197/+359) of the ESR2 gene. Bisulfite sequencing of this region showed significantly higher methylation in primary endometrial cells (n = 8 subjects) versus endometriotic cells (n = 8 subjects). The demethylating agent 5-aza-2'-deoxycytidine significantly increased ESR2 mRNA levels in endometrial cells. Mechanistically, we employed serial deletion mutants of the ESR2 promoter fused to the luciferase reporter gene and transiently transfected into both endometriotic and endometrial cells. We demonstrated that the critical region (-197/+372) that confers promoter activity also bears the CpG island, and the activity of the ESR2 promoter was strongly inactivated by in vitro methylation. Taken together, methylation of a CpG island at the ESR2 promoter region is a primary mechanism responsible for differential expression of ESR2 in endometriosis and endometrium. These findings may be applied to a number of areas ranging from diagnosis to the treatment of endometriosis.


[Venous thrombosis from central venous catheterization in oncology].
The aim of this review article is to assess the epidemiology, diagnosis and treatment of deep venous thrombosis of the upper limbs which are becoming more common with the use of central catheterizations in oncology. The incidence is differently estimated. The catheterization is the main risk factor which is added to the proper patient's risk factors in a highly thrombogenic context (cancer, chemotherapy, infection,...). The outcome can be limited to the catheter (thrombotic) dysfunction or can progress towards vein thrombosis, pulmonary embolism, most often asymptomatic or to a superior vena cava syndrome. Ultrasounds and CT scan have an important role although their efficacy have not been demonstrated yet. Prophylactic anticoagulation with unfractionated heparin, low molecular weight heparin or oral anticoagulant seems to be effective. Low dose thrombolysis by bolus of urokinase or tissue plasminogen activator allows restoring the patency of the catheter in 70 to 90% cases of thrombotic dysfunction. The modalities of treatment of the vein thrombosis are much discussed.


Role of T cells in malnutrition and obesity.
Nutritional status is critically important for immune cell function. While obesity is characterized by inflammation that promotes metabolic syndrome including cardiovascular disease and insulin resistance, malnutrition can result in immune cell defects and increased risk of mortality from infectious diseases. T cells play an important role in the immune adaptation to both obesity and malnutrition. T cells in obesity have been shown to have an early and critical role in inducing inflammation, accompanying the accumulation of inflammatory macrophages in obese adipose tissue, which are known to promote insulin resistance. How T cells are recruited to adipose tissue and activated in obesity is a topic of considerable interest. Conversely, T cell number is decreased in malnourished individuals, and T cells in the setting of malnutrition have decreased effector function and proliferative capacity. The adipokine leptin, which is secreted in proportion to adipocyte mass, may have a key role in mediating adipocyte-T cell interactions in both obesity and malnutrition, and has been shown to promote effector T cell function and metabolism while inhibiting regulatory T cell proliferation. Additionally, key molecular signals are involved in T cell metabolic adaptation during nutrient stress; among them, the metabolic regulator AMP kinase and the mammalian target of rapamycin have critical roles in regulating T cell number, function, and metabolism. In summary, understanding how T cell number and function are altered in obesity and malnutrition will lead to better understanding of and treatment for diseases where nutritional status determines clinical outcome.


Kissing right? On the consistency of the head-turning bias in kissing.
The present study investigated the consistency of the head-turning bias in kissing. In particular we addressed what happens if a person who prefers to kiss with the head turned to the right kisses a person who prefers to kiss with the head turned to the left. To this end, participants (N=57) were required to kiss a life-sized doll's head rotated in different orientations that were either compatible or incompatible with the participants' head-turning preference. Additionally, participants handedness, footedness, and eye preference was assessed. Results showed that a higher percentage of participants preferred to kiss with their head turned to the right than to the left. In addition, the right-turners were more consistent in their kissing behaviour than left-turners. That is, with the doll's head rotated in an incompatible direction, right-turners were less likely to switch their head to their non-preferred side. Since no clear relationships between head-turning bias and the other lateral preferences (i.e., handedness, footedness, and eye preference) were discerned, the more consistent head-turning bias among right-turners could not be explained as deriving from a joint pattern of lateral preferences that is stronger among individuals with rightward as compared to individuals with leftward lateral preferences.


Astrocyte Specificity and Coverage of hGFAP-CreERT2 [Tg(GFAP-Cre/ERT2)13Kdmc] Mouse Line in Various Brain Regions.
Astrocyte is the most abundant cell type in the central nervous system and its importance has been increasingly recognized in the brain pathophysiology. To study in vivo function of astrocyte, astrocyte-specific gene-targeting is regarded as a powerful approach. Especially, hGFAP-CreERT2, which expresses tamoxifen-inducible Cre recombinase under the human GFAP promoter, has been developed and characterized from several research groups. However, one of these mouse lines, [Tg(GFAP-Cre/ERT2)13Kdmc] from Ken McCarthy group has not been quantitatively analyzed, despite its frequent use. Here, we performed comprehensive characterization of this mouse line with quantitative analysis. By crossing this mouse line with Ai14 (RCL-tdTomato), a very sensitive Cre reporter mouse line, we visualized the Cre-expressing cells in various brain regions. For quantitative analysis, we immunostained S100β as an astrocytic marker and NeuN, tyrosine hydroxylase or calbindin as a neuronal marker in different brain regions. We calculated 'astrocyte specificity' as the proportion of co-labelled S100β and tdTomato positive cells in the total number of tdTomato positive cells and the 'astrocyte coverage' as the proportion of co-labelled S100β and tdTomato positive cells in the total number of S100β positive cells. Interestingly, we found varying degree of astrocyte specificity and coverage in each brain region. In cortex, hypothalamus, substantia nigra pars compacta and cerebellar Purkinje layer, we observed high astrocyte specificity (over 89%) and relatively high astrocyte coverage (over 70%). In striatum, hippocampal CA1 layer, dentate gyrus and cerebellar granule layer, we observed high astrocyte specificity (over 80%), but relative low astrocyte coverage (50-60%). However, thalamus and amygdala showed low astrocyte specificity (about 65%) and significant neuron specificity (over 30%). This hGFAP-CreERT2 mouse line can be useful for genetic modulations of target gene either in gain-of-function or loss-of-function studies in the brain regions with high astrocyte specificity and coverage. However, the use of this mouse line should be restricted to gain-of-function studies in the brain regions with high astrocyte specificity but low coverage. In conclusion, hGFAP-CreERT2 mouse line could be a powerful tool for gene-targeting of astrocytes in cortex, striatum, hippocampus, hypothalamus, substantia nigra pars compacta and cerebellum, but not in thalamus and amygdala.


Cesarean delivery in preeclampsia and seasonal variation in a tropical rainforest belt.
The pathogenesis of preeclampsia is poorly understood and recent evidence suggests that the incidence varies depending upon the season. This study was carried out to determine whether there is a seasonal variation in the presentation of preeclamptics undergoing cesarean delivery in a tropical rainforest belt. A university teaching hospital. Retrospective. The hospital records of consecutive patients (July 1996-June 2006) with preeclampsia, who underwent cesarean delivery in a tertiary care centre, were reviewed. Data collected included patient demographics, total number of deliveries, number of cesarean deliveries, and number of preeclampsia patients and time of presentation for cesarean section. Approval of the local ethical committee was obtained. The EPI info software program was used for statistical analysis. A total of 6798 deliveries were recorded during the study period resulting in 6485 live births. There were 1579 cesarean deliveries during the period. Of these, 196 patients had toxemia of pregnancy (166 with preeclampsia and 30 with eclampsia). One hundred and forty-one patients (9% of cesarean deliveries) had cesarean delivery during the rainy season and 55 (3.5%) during the dry season (P < 0.05). Amongst preeclampsia patients, 115 presented (7%) during the rainy season and 51 (3.2%) during the dry season (P < 0.05). In the eclampsia group, 26 (1.65% of cesarean sections) presented during the rainy season and four (0.25%) during the dry season (P < 0.05). There was a seasonal variation in the cesarean delivery required for preeclampsia/eclampsia patients. This may help in counseling women on when to plan their pregnancy in order to reduce the morbidity and mortality associated with this apparent seasonal disease.


[Errors in forensic medical activities].
The comparative structural and systemic analysis of 303 forensic medical expert conclusion (acts) made it possible to reveal and systematize errors encountered in forensic medical practice at the stages of investigation, interpretation, and estimation of the obtained results. The authors distinguish between performance errors and cognitive errors in the course of forensic medical expertise. The definition of the notion of "expert error" is proposed. The process of error analysis is described with special reference to forensic medical activities.


Characterization of a human squamous carcinoma cell line resistant to cis-diamminedichloroplatinum(II).
We have developed a human head and neck squamous cell carcinoma cell line (SCC-25/CP) which is relatively stably resistant to cis-diamminedichloroplatinum(II) (CDDP) after repeated exposure to escalating doses of the drug. The studies reported elucidate the mechanism(s) by which the SCC-25/CP cell line is resistant to CDDP. The SCC-25/CP cell line is approximately 30-fold resistant to CDDP, approximately 10-fold resistant to carboplatin, and about 9-fold resistant to iproplatin. Using [195mPt]CDDP, we examined the levels of platinum in whole cells and cellular fractions of both the SCC-25 and SCC-25/CP cells after 1 h exposure to 100 microM drug. The SCC-25 cells took up 30 pmol of platinum/10(6) cells in 1 h; 64% of the drug was in the nucleus and 21% in the cytosol. The SCC-25/CP cells took up 7 pmol of platinum/10(6) cells; of this, 41% was in the nucleus and 33% in the cytosol. The SCC-25 cell nuclei contained 331 pmol of platinum/mg protein and the cytosol 21 pmol of platinum/mg protein, whereas the SCC-25/CP cell nuclei contained 47 pmol of platinum/mg protein and the cytosol 8.1 pmol/mg protein. The release of drug from both cell lines followed a very similar course and was most rapid over the first 6 h. There was no difference in the non-protein sulfhydryl content of the cell lines. The protein sulfhydryl content, as measured by Ellman's procedure, indicated that the SCC-25/CP cell line has approximately a 2-fold increase in protein sulfhydryl content compared to the SCC-25 cell line. The SCC-25/CP cell line is about 2-fold resistant to cadmium chloride at 50% cell kill and about 2.5-fold resistant at 1 log kill compared to the SCC-25 cell line. Glutathione transferase activity in crude cytoplasmic extracts was measured and found to be approximately 2- to 3-fold higher in the CDDP resistant cells. The isoelectric point of the glutathione transferase isozyme was 4.8 in both the sensitive and resistant cell lines, suggesting induction of the predominant isozyme present in the parent cell line. By alkaline elution there was greater cross-link formation by CDDP in the SCC-25 cell line than in the SCC-25/CP cell line at the same drug concentrations. In conclusion, the mechanism of resistance of the SCC-25/CP cell line to CDDP is multifactorial, involving plasma membrane changes, increased cytosolic binding, and decreased DNA cross-linking.


Herbal Acupuncture for the Treatment of Obesity.
Obesity is the state of excessive body fat accumulation and is mainly caused by consuming more calories than are burned through physical activity. Herbal acupuncture (HA), also known as pharmacopuncture, has been increasingly used in clinics of Korean medical to alleviate obesity. This review analyzed four clinical studies and 16 animal studies on the effectiveness of HA as a treatment for obesity. Clinical evidence suggests that various kinds of HA might be beneficial for treating obesity; however, further investigations with well-designed, evidence-based, randomized clinical trials are needed. Animal studies support the idea that HA might be beneficial for the treatment of obesity and provide possible mechanisms, such as anti-inflammation, antioxidation, modulating lipid metabolism and so on, to explain the effect of HA on obesity. This review, based on the evidence collected, suggests that HA could have a beneficial effect for alleviating obesity by modulating inflammation, oxidative stress, lipid metabolism, leptin, and the insulin signal.


[State-of-the-art of trans-vitreal surgery of the eye].
The modern condition of endo- and transvitreal surgery of the eye was demonstrated with regard for surgical approaches, technical outfit, expendables and medical preparations. Variants of clinical application of vitreal surgery methods at different pathologies of the vitreous body and retina, e.g. haemophthalmos of various etiologies, opacity of the vitreous body (including that of the uveal origin, proliferative diabetic retinopathy) diabetic macular edema, proliferative vitreoretinopathy of other etiologies (including complicated retinal detachments, posttraumatic vitreoretinopathy), complicated cataract extraction, macular pathology (including traction deformation of the retinal surface, senile macular holes and sub-retinal neovascular membranes) are discussed.


Endoscopic laser palliation of malignant dysphagia: a prospective study.
We prospectively studied the short-term and long-term efficacy and safety of endoscopic laser treatment in 25 patients with dysphagia from advanced esophageal cancer. Malignant stenoses were recanalized in all patients, and the ability to swallow was improved in about 80%. Results were best in patients with adenocarcinomas and in those who reported a good appetite. A single laser treatment provided adequate palliation in more than half the patients until the time of death. In those patients in whom stenosis recurred, re-treatment was necessary a median of 3.2 months after the initial laser treatment. No laser-related mortality or major morbidity occurred. We conclude that endoscopic laser therapy seems to be a feasible method of palliating malignant dysphagia.


Tektites that were partially plastic after completion of surface sculpturing.
Among the 50,000 tektites collected over an 8-year period as part of a representative collection of the indochinities in an area near Dalat, South Vietnam, several individual ones have been found that show evidence of having been internally plastic after surface sculpturing was essentially completed. Two drops, which were bent after having formed a thin exterior skin or crust, exhibit surface breaks and stretching of their plastic interiors within the breaks. The lack of deep sculpturing in this interior stretched area, coupled with twisting within the break on one of them, indicates that the surface features on these tektites were formed in the atmosphere and not by etching by soil acids, as had been widely believed.


[Evaluation of patients presenting with a suspicion of cystic echinococcosis to the serology laboratory of the Parasitology Department of Dokuz Eylül University Medical Faculty].
Cystic echinococcosis (CE) is a zoonosis, caused by the metacestode form of Echinococcus granulosus. The diagnosis of CE is difficult using the clinical features of the disease and it depends on the combination of serological methods aimed at determining the specific antibody response and on imaging techniques that support the serology. In this study, 465 patients who presented with a suspicion of CE to the serology laboratory of the Parasitology Department of Dokuz Eylul University between January 2003 and June 2004 were evaluated. The specific anti-E. granulosus antibodies in the serum samples of patients were examined by an in-house enzymelinked immunosorbent assay (ELISA) test and a commercial indirect hemagglutination (IHA) test. Seventy eight (17%) of the patients were positive with ELISA and 65 (14%) of them were positive with IHA with varying titrations. Fifty six (12%) of the sera were positive with both methods. Fifty-six of the eighty patients who underwent CE surgery at different times before this study were found to be seropositive, while the remaining 24 were found to be seronegative. We concluded that it is very important to combine at least two methods in the serological diagnosis of CE.


Hypertension and diabetes: new therapeutic options.
The treatment of high-risk hypertensive patients with diabetes presents clinicians with challenges and opportunities. The coexistence of hypertension and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications. Perhaps most important among these is the increased risk of cardiovascular events in this patient population, an observation that can be best appreciated by the increased number of deaths attributed to cardiovascular-related diseases in diabetic patients aged 45 to 65 years. Consequently, aggressive therapy in this population offers the promise of significantly reducing excess cardiovascular deaths. Despite this opportunity for reducing mortality in these high-risk patients, several challenges to treatment remain. While aggressive blood pressure reduction has been documented to reduce the rate of events in these patients, questions remain as to the level to which blood pressure should be reduced. The recent guidelines from the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure emphasized the importance of treating patients with hypertension and diabetes as if they already have target organ damage. Low blood pressure targets of 130/85 mm Hg, with an optimal goal of 120/80 mm Hg, can reduce the risk of events in hypertensive patients with diabetes, regardless of the pharmacological means used. However, there are physiologic and clinical rationale for renin angiotensin system blockade, with angiotensin-converting enzyme inhibition as the preferential therapy in these patients. In this regard, preliminary data with the new class of angiotensin II receptor blockers suggest that these agents may offer benefits equivalent to those observed with angiotensin-converting enzyme inhibitors while offering better tolerance.


Altered DNA methylation underlies monocyte dysregulation and innate exhaustion memory in sepsis.
Innate immune memory is the process by which pathogen exposure elicits cell-intrinsic states to alter the strength of future immune challenges. Such altered memory states drive monocyte dysregulation during sepsis, promoting pathogenic behavior characterized by pro-inflammatory, immunosuppressive gene expression in concert with emergency hematopoiesis. Epigenetic changes, notably in the form of histone modifications, have been shown to underlie innate immune memory, but the contribution of DNA methylation to this process remains poorly understood. Using an ex vivo sepsis model, we discovered broad changes in DNA methylation throughout the genome of exhausted monocytes, including at several genes previously implicated as major drivers of immune dysregulation during sepsis and Covid-19 infection (e.g. Plac8 ). Methylome alterations are driven in part by Wnt signaling inhibition in exhausted monocytes, and can be reversed through treatment with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. Importantly, these changes are recapitulated in septic mice following cecal slurry injection, resulting in stable changes at critical immune genes that support the involvement of DNA methylation in acute and long-term monocyte dysregulation during sepsis.


Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications.
Semaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA). Soluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme-linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS-4-treated monocytic cell line (THP-1 cells). The efficacy of anti-Sema4D antibody was evaluated in mice with collagen-induced arthritis (CIA). Levels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D-expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS-4 cleaved cell surface Sema4D to generate sSema4D in THP-1 cells. Soluble Sema4D induced tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) production from CD14+ monocytes. IL-6 and TNFα induced ADAMTS-4 expression in synovial cells. Treatment with an anti-Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA. A positive feedback loop involving sSema4D/IL-6 and TNFα/ADAMTS-4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti-Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA.


The Phlebotomine sand fly fauna of Switzerland revisited.
Sand flies (Diptera: Psychodidae, Phlebotominae; Newstead, 1911) are widespread in Europe, being particularly common in the Mediterranean region but rare north of the Alps. Thus, Switzerland is an opportune place to investigate the sand fly fauna on both sides of the Alpine crest, in southern sub-Mediterranean climate and northern oceanic temperate climate. We reinvestigated the Swiss sand fly fauna with the aim to assess changes in composition, altitudinal distribution, abundance and seasonality. Thirty-eight sites were investigated with light traps and/or interception sticky traps in 4 years. Ninety and 380 specimens were caught by light traps and sticky traps, respectively, at 15 collecting sites. Four species were identified. Phlebotomus mascittii (Grassi, 1908), Phlebotomus perniciosus (Newstead, 1911) and Sergentomyia minuta (Rondani, 1843) were confirmed in Ticino, and P. mascittii for the first time in neighbouring Grisons. Also, Phlebotomus neglectus (Tonnoir, 1921) is for the first time reported, though at a very low density compared to P. perniciosus at the same site. Its presence in Ticino supports the northward spread observed in Italy. Sand flies were detected north of the Alps at one site only, endorsing a historical report. Overall, the low density of P. perniciosus and very low density of P. neglectus suggest that canine leishmaniosis may not be an important disease risk in Switzerland.


Theoretical study on the effect of applying an external static electric field on the singlet fission dynamics of pentacene dimer models.
We investigate the effect of applying an external static electric field on the singlet fission (SF) dynamics of pentacene dimer models using quantum chemical calculations and exciton dynamics simulations. It is found that the excitation energies of anion-cation (AC) and cation-anion (CA) pair exciton states in the SF process are significantly stabilized and destabilized, respectively, by applying an external static electric field (F) in the intermolecular direction. As a result, this change of excitation energies is found to accelerate the SF dynamics in pentacene dimer models. In particular, in the tilted- and parallel-type pentacene dimer models, SF rates at F = 0.001 a.u. are predicted to be about 2.3 and 3.0 times as large as those at F = 0.0 a.u. while keeping the TT yields large. The present result contributes to paving the way for novel physical and chemical controls, that is, an external static electric field application and donor/acceptor substitution on SF molecules, of SF dynamics.


Developmental Population Pharmacokinetics-Pharmacodynamics of Meropenem in Chinese Neonates and Young Infants: Dosing Recommendations for Late-Onset Sepsis.
The pharmacokinetic (PK) studies of meropenem in Chinese newborns with late-onset sepsis (LOS) are still lacking. Causative pathogens of LOS and their susceptibility patterns in China differ from the data abroad. We, therefore, conducted a developmental population pharmacokinetic−pharmacodynamic analysis in Chinese newborns with the goal to optimize meropenem dosing regimens for LOS therapy. An opportunistic sampling strategy was used to collect meropenem samples, followed by model building and validation. A Monte Carlo simulation was performed to show the probability of target attainment (PTA) for various dosages. The information from 78 newborns (postmenstrual age: 27.4−46.1 weeks) was compiled and had a good fit to a 1-compartment model that had first order elimination. The median (range) values of estimated weight−normalized volume of distribution (V)and clearance (CL) were 0.60 (0.51−0.69) L/kg and 0.16 (0.04−0.51) L/h/kg, respectively. Covariate analysis revealed that postnatal age (PNA), gestational age (GA) and current weight (CW) were the most important factors in describing meropenem PK. Simulation results showed for LOS with a minimal inhibitory concentration (MIC) of 8 mg/L, the doses of 30 mg/kg 3 times daily (TID) as a 1-h infusion for newborns with GA ≤ 37 weeks and 40 mg/kg TID as a 3-h infusion for those with GA > 37 weeks were optimal, with PTA of 71.71% and 75.08%, respectively. In conclusion, we proposed an evidence-based dosing regimen of meropenem for LOS in Chinese newborns by using the population pharmacokinetic−pharmacodynamic analysis, based on domestic common pathogens and their susceptibility patterns.


Simple strategy for the immobilization of dirhodium tetraprolinate catalysts using a pyridine-linked solid support.
Dirhodium tetracarboxylates are readily immobilized on agitation in the presence of highly cross-linked polystyrene resins with a pyridine attachment. A systematic study demonstrates that the polymer backbone, the linker, the terminal pyridine group, and the catalyst structure all contribute to the efficiency of dirhodium catalyst immobilization. The immobilization is considered to be due to the combination of ligand coordination and encapsulation. The dirhodium tetraprolinate catalysts, Rh2(S-DOSP)4 (1a), Rh2(S-TBSP)4 (1b), and Rh2(S-biTISP)2 (2), are all efficiently immobilized. The resulting heterogeneous complexes are very effective catalysts for asymmetric cyclopropanation between methyl phenyldiazoacetate and styrene, and under optimized conditions they can be recycled five times with virtually no loss in enantioselectivity. The three-phase test studies indicated that a very slow reaction occurs when both the catalyst and the diazo compound were immobilized, but the slow rate precluded the likelihood that the cyclopropanation was predominately occurring by a release-and-capture mechanism.


Peripheral blood mononuclear cells HIV DNA levels impact intermittently on neurocognition.
To determine the contribution of peripheral blood mononuclear cells' (PBMCs) HIV DNA levels to HIV-associated dementia (HAD) and non-demented HIV-associated neurocognitive disorders (HAND) in chronically HIV-infected adults with long-term viral suppression on combined antiretroviral treatment (cART). Eighty adults with chronic HIV infection on cART (>97% with plasma and CSF HIV RNA <50 copies/mL) were enrolled into a prospective observational cohort and underwent assessments of neurocognition and pre-morbid cognitive ability at two visits 18 months apart. HIV DNA in PBMCs was measured by real-time PCR at the same time-points. At baseline, 46% had non-demented HAND; 7.5% had HAD. Neurocognitive decline occurred in 14% and was more likely in those with HAD (p<.03). Low pre-morbid cognitive ability was uniquely associated with HAD (p<.05). Log10 HIV DNA copies were stable between study visits (2.26 vs. 2.22 per 106 PBMC). Baseline HIV DNA levels were higher in those with lower pre-morbid cognitive ability (p<.04), and higher in those with no ART treatment during HIV infection 1st year (p = .03). Baseline HIV DNA was not associated with overall neurocognition. However, % ln HIV DNA change was associated with decline in semantic fluency in unadjusted and adjusted analyses (p = .01-.03), and motor-coordination (p = .02-.12) to a lesser extent. PBMC HIV DNA plays a role in HAD pathogenesis, and this is moderated by pre-morbid cognitive ability in the context of long-term viral suppression. While the HIV DNA levels in PBMC are not associated with current non-demented HAND, increasing HIV DNA levels were associated with a decline in neurocognitive functions associated with HAND progression.


Interpretation of blood pressure signal: physiological bases, clinical relevance, and objectives during shock states.
Achievement of a mean blood pressure (MBP) target is one of the hemodynamic goals to ensure an adequate blood perfusion pressure in critically ill patients. Arterial catheter allows for a continuous and precise monitoring of arterial pressure signal. In addition to giving a precise MBP monitoring, analysis of the blood pressure wave provides information that may help the clinician to interpret hemodynamic status. The interpretation of BP wave requires the understanding of simple principles. In this review, we first discuss the physiological mechanism responsible for arterial pressure generation. We then emphasize the interpretation of the static indexes and the dynamic indexes generated by heart-lung interactions derived from arterial pressure wave. Finally, we focus on MBP value as a therapeutic target in critically ill patients. We discuss the recommended target MBP value by reviewing available data from experimental and clinical studies.


Cross-cultural applicability of the episodic disability framework with adults living with HIV in Ireland: a qualitative study.
Purpose: To explore the cross-cultural applicability of the Episodic Disability Framework with people living with HIV in Ireland.Methods: We conducted a qualitative descriptive study using semi-structured interviews. We recruited adults with HIV from a hospital clinic and community-based organization in Dublin, Ireland. We asked participants to describe their health-related challenges, the extent to which these challenges were episodic in nature, and the impact on their overall health. We analyzed data using content analytical techniques.Results: Of the 12 participants (9 men; 3 women), with a median time since HIV diagnosis of 12 years, 83% had an undetectable viral load. Participants described multi-dimensional and episodic health challenges that spanned disability dimensions in the Episodic Disability Framework including: physical, cognitive, and mental-emotional symptoms and impairments, challenges to social inclusion, and uncertainty or worrying about future health with HIV. Contextual factors that exacerbated disability included stigma and fear of HIV disclosure whereas living strategies (lifestyle, positive outlook, resiliency) and social support (family, friends, health services and providers) mitigated disability.Conclusions: The Episodic Disability Framework is pertinent to adults living with HIV in Ireland. Contextual factors are critical for understanding cross-cultural distinctions of the disability experience across varying political, economic, socio-cultural, and environmental contexts and should be considered by rehabilitation professionals to address disability for people with HIV.Implications for rehabilitationThe Episodic Disability Framework, originally derived and validated from perspectives of adults living with HIV in Canada, is pertinent to people living with HIV in Ireland.The Episodic Disability Framework can be used to describe disability experienced by people living with HIV, and to better understand the contextual factors that may exacerbate or alleviate dimensions of disability over time.Contextual factors are critical for understanding cross-cultural distinctions of the disability experience across varying political, economic, sociocultural, and environmental contexts, and should be considered by rehabilitation professionals to better address disability for people with HIV.


Methylation of the CA9 promoter can modulate expression of the tumor-associated carbonic anhydrase IX in dense carcinoma cell lines.
CA IX is a tumor-associated transmembrane isoform of the carbonic anhydrase with a high enzyme activity and a functional involvement in the pH regulation and cell adhesion. Expression of CA9 gene in tumor cells is principally regulated by the high cell density and the hypoxia-related VHL-HIF pathway. In renal cell carcinomas with VHL inactivation, CA9 transcription is further controlled by site-specific promoter methylation. Here we explored a possible role of methylation in the non-RCC cell lines represented mainly by HeLa cervical carcinoma cells. Using metabisulfite sequencing and treatment with the methylation inhibitor 5-aza-2'-deoxycytidine we showed that the methylation of a single CpG site at -74 position with respect to the transcription start can down-modulate the expression of CA9 in cells cultivated at high density, but not in cells grown in sparse culture nor in cells exposed to hypoxia. Methylation appears to act in tumor cells expressing intermediate levels of CA IX protein, but not in cell lines expressing high CA IX levels. Our results indicate that promoter methylation is not crucial for the control of CA9 gene expression in the non-RCC cell lines but could represent an accessory mechanism restricting its expression in highly dense carcinoma cell cultures.


The role of PPARγ-mediated signalling in skin biology and pathology: new targets and opportunities for clinical dermatology.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that modulate the expression of multiple different genes involved in the regulation of lipid, glucose and amino acid metabolism. PPARs and cognate ligands also regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. This includes a role in mediating skin and pilosebaceous unit homoeostasis: PPARs appear to be essential for maintaining skin barrier permeability, inhibit keratinocyte cell growth, promote keratinocyte terminal differentiation and regulate skin inflammation. They also may have protective effects on human hair follicle (HFs) epithelial stem cells, while defects in PPARγ-mediated signalling may promote the death of these stem cells and thus facilitate the development of cicatricial alopecia (lichen planopilaris). Overall, however, selected PPARγ modulators appear to act as hair growth inhibitors that reduce the proliferation and promote apoptosis of hair matrix keratinocytes. The fact that commonly prescribed PPARγ-modulatory drugs of the thiazolidine-2,4-dione class can exhibit a battery of adverse cutaneous effects underscores the importance of distinguishing beneficial from clinically undesired cutaneous activities of PPARγ ligands and to better understand on the molecular level how PPARγ-regulated cutaneous lipid metabolism and PPARγ-mediated signalling impact on human skin physiology and pathology. Surely, the therapeutic potential that endogenous and exogenous PPARγ modulators may possess in selected skin diseases, ranging from chronic inflammatory hyperproliferative dermatoses like psoriasis and atopic dermatitis, via scarring alopecia and acne can only be harnessed if the complexities of PPARγ signalling in human skin and its appendages are systematically dissected.


A phase II study to determine the efficacy and tolerability of intravenous ZD9331 in heavily pretreated patients with ovarian cancer.
This Phase II, multicenter, open-label study was conducted to assess the efficacy and tolerability of ZD9331, a novel direct-acting thymidylate synthase inhibitor, in heavily pretreated patients with ovarian cancer. The study recruited 44 women with ovarian cancer or primary peritoneal cancer previously treated with platinum therapy and paclitaxel and with progressive disease after, or intolerance to, topotecan administered as the most recent therapy. ZD9331 was administered as an intravenous infusion at 130 mg/m(2) on Days 1 and 8 of 3-week cycles, until objective evidence of disease progression. A cutoff date of 3 months after the last patient received the first dose was set for data collection. Patients received a mean of 3.3 cycles of ZD9331 and a total of 143 cycles were administered. Among the 42 patients evaluated for best overall tumor response, one achieved a complete response and two achieved a partial response, giving an objective tumor response rate of 7%. The complete response occurred at Day 15 of Cycle 2 in a patient receiving ZD9331 as her eighth-line therapy. Seven patients had stable disease, giving a disease control rate of 23%. Thirty-one patients (71%) had disease progression and the median time to progression was 53 days. Most patients (89%) experienced drug-related adverse events, most commonly nausea (73%), vomiting (48%), and neutropenia (50%). Six patients (14%) were withdrawn from treatment due to adverse events. The preliminary evidence of efficacy and acceptable tolerability of ZD9331 in this heavily pretreated population with ovarian cancer warrants further investigation, especially in a less heavily pretreated patient population.


Structural mechanism of two gain-of-function cardiac and skeletal RyR mutations at an equivalent site by cryo-EM.
Mutations in ryanodine receptors (RyRs), intracellular Ca2+ channels, are associated with deadly disorders. Despite abundant functional studies, the molecular mechanism of RyR malfunction remains elusive. We studied two single-point mutations at an equivalent site in the skeletal (RyR1 R164C) and cardiac (RyR2 R176Q) isoforms using ryanodine binding, Ca2+ imaging, and cryo-electron microscopy (cryo-EM) of the full-length protein. Loss of the positive charge had greater effect on the skeletal isoform, mediated via distortion of a salt bridge network, a molecular latch inducing rotation of a cytoplasmic domain, and partial progression to open-state traits of the large cytoplasmic assembly accompanied by alteration of the Ca2+ binding site, which concur with the major "hyperactive" feature of the mutated channel. Our cryo-EM studies demonstrated the allosteric effect of a mutation situated ~85 Å away from the pore and identified an isoform-specific structural effect.


Investigations into the effect of acid on the spectral and kinetic properties of purple membrane from Halobacterium halobium.
The formation and reversal of the acid species of purple membrane generated below pH 4.00 (22 degrees C) is studied together with the photochemical cycle over the pH range 6.40--3.20. The buffering capacity of the membrane reaches a peak at pH 4.30, indicating the possibility of a conformational change taking place. The generation of the new spectral species can take place in the dark and is unaffected by the addition of reducing agents. Kinetic parameters measured indicate that the group being titrated below pH 4.00 could be the same as that protonated in the formation of intermediate O. The temporal placement of intermediate O after M in the photochemical cycle is shown to be incompatible with the data presented here. Reneutralization of acidified purple membrane shows that the spectral changes in acid are reversible but the phototransient properties are altered.


Detection of DNA probes using Diels Alder cycloaddition and SERRS.
A number of methods for detecting specific DNA sequences have been used to provide data for use in diagnosis of disease states and examination of gene expression. This study shows how the use of labelled oligonucleotides created by Diels Alder cycloaddition can be used as surface enhanced resonance Raman scattering (SERRS) active probes that provide easily identifiable signals at low concentrations in a mixture. The probes were produced by first tagging the oligonucleotides with a furan residue at the 5'-terminus to act as the diene. Three specifically designed benzotriazole azo maleimide dyes were then used as dienophiles to undergo cycloaddition with the furan modified oligonucleotide to generate SERRS active probes. These probes gave excellent SERRS signals from a silver-PVA film. Surface mapping of the silver PVA film indicated that the distribution of the dyes was uniform and that the number of moles of probe detected at any one time was approximately in the attomole region.


A review of climate change impacts on the ecosystem services in the Saami Homeland in Finland.
The aim of this work is (i) to review the recent studies on weather and climate change in Finnish Sápmi and to present the literature review findings alongside our survey on the observations made by local reindeer herders on the same phenomena, and, further, (ii) to review the impacts of climate change on the ecosystem services (ES) in Finnish Sápmi. The focus of the study is on the impacts of climate change on those habitat, provisioning and cultural ecosystem services which are interconnected with the Saami way of life as Indigenous people and thus support the continuity of their culture. In the holistic world view of Arctic Indigenous peoples, material culture and non-material culture are not separated, and there is no boundary between nature and culture. However, cultural and spiritual meanings of ecosystems, species and landscapes are rarely taken into account in scientific research on ecosystems services. Our review indicates that mostly negative impacts of climate warming on ecosystems and traditional livelihoods are to be expected in Sápmi. The most profound negative impacts will be on palsa mire and fell ecosystems, in particular snowbeds, snow patches and mountain birch forests. Consequently, changes in ecosystems may erode cultural meanings, stories, memories and traditional knowledge attached to them and affect the nature-based traditional livelihoods. In a situation where our rapidly changing climate is affecting the foundations of the nature-based cultures, the present review can provide a knowledge base for developing adaptation actions and strategies for local communities and Indigenous peoples to cope with changes caused by climate change and other drivers.


Clinical diversity in adult T-cell leukemia-lymphoma.
Adult T-cell leukemia-lymphoma (ATL) is a unique T-cell cancer first described in Japan. We estimate that more than 200 patients a year have been detected in Kyushu. The surface phenotype of ATL cells characterized by monoclonal antibodies is T3+, T4+, T8-, T11+, and Tac+. In all cases the serum is positive for anti-human T-cell leukemia (lymphotropic) virus (HTLV-I) antibodies and the ATL cells contain the proviral DNA of HTLV-I. Variations in the clinical features of atypical cases suggest a division of the spectrum of ATL into five types: acute (prototypic), chronic, smoldering, crisis, and lymphoma. Screening of the sera from healthy adults for presence of the anti-HTLV-I antibodies revealed that 3.6% of healthy individuals in Kumamoto Prefecture, which is located in the middle of Kyushu, were HTLV-I carriers. The percentage of positivity increased with age and was higher in females than in males. It varied from town to town, ranging from 0 to 17.6%. Family studies showed that the routes of natural infection of HTLV-I are from mother to child and also from husband to wife. The third route is blood transfusion. The borderline between the healthy carrier state and smoldering ATL remains unclear. In the endemic areas smoldering ATL is frequently diagnosed in patients with fungus infection of the skin, chronic lymphadenopathy, interstitial pneumonitis, chronic renal failure, and strongyloidiasis. In addition our experiences with a concurrence of lymphoma-type ATL in three sisters and spontaneous remissions in a patient with chronic ATL are cited.


Abnormal melatonin receptor 1B expression in osteoblasts from girls with adolescent idiopathic scoliosis.
Melatonin signaling dysfunction has been associated with the etiology of adolescent idiopathic scoliosis (AIS). Genetic analysis has also associated the occurrence of AIS with the MT2 gene. Thus, we determined whether there is abnormality in the protein expression of melatonin receptors (MT) in AIS osteoblasts. In this study, we recruited 11 girls with severe AIS and eight normal subjects for intraoperative bone biopsies. MT1 and MT2 receptor protein expressions in the isolated osteoblasts were detected. Also, cell proliferation assay using different melatonin concentrations (0, 10(-9), 10(-5), 10(-4) m) was carried out. The results showed that both MT1 and MT2 receptors are expressed in osteoblasts of the controls. While MT1 receptors were expressed in osteoblasts of all AIS subjects, osteoblasts of only 7 of 11 AIS showed expression of MT2 receptors. Melatonin stimulated control osteoblasts to proliferate. However, proliferation of AIS osteoblasts without expression of MT2 receptor, after treatment with melatonin, was minimal when compared with control and AIS osteoblasts with MT2 receptor expression. The proliferation of AIS osteoblasts with MT2 receptor was greater than those without. This is the first report demonstrating a difference between AIS and normal osteoblasts in the protein expression of MT2 receptor. The results suggest that there is a possible functional effect of MT2 receptor on osteoblast proliferation. AIS osteoblasts without expression of MT2 receptor showed the lowest percentage of viable cells after melatonin treatment. This possibly indicates the modulating role of melatonin through MT2 receptor on the proliferation of osteoblasts.


Endogenous progesterone levels and frontotemporal dementia: modulation of TDP-43 and Tau levels in vitro and treatment of the A315T TARDBP mouse model.
Frontotemporal dementia (FTD) is associated with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Together, this group of disorders constitutes a major cause of young-onset dementia. One of the three clinical variants of FTD is progressive nonfluent aphasia (PNFA), which is focused on in this study. The steroid hormone progesterone (PROG) is known to have an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum samples (39 FTD, 91 controls), low serum PROG was associated with FTD overall. In subgroup analysis, low PROG levels were significantly associated with FTD-MND and CBS, but not with PSPS or PNFA. PROG levels of >195 pg/ml were significantly correlated with lower disease severity (frontotemporal dementia rating scale) for individuals with CBS. In the human neuroblastoma SK-N-MC cell line, exogenous PROG (9300-93,000 pg/ml) had a significant effect on overall Tau and nuclear TDP-43 levels, reducing total Tau levels by ∼1.5-fold and increasing nuclear TDP-43 by 1.7- to 2.0-fold. Finally, elevation of plasma PROG to a mean concentration of 5870 pg/ml in an Ala315Thr (A315T) TARDBP transgenic mouse model significantly reduced the rate of loss of locomotor control in PROG-treated, compared with placebo, mice. The PROG treatment did not significantly increase survival of the mice, which might be due to the limitation of the transgenic mouse to accurately model TDP-43-mediated neurodegeneration. Together, our clinical, cellular and animal data provide strong evidence that PROG could be a valid therapy for specific related disorders of FTD.


Olive leaf tea is beneficial for lipid metabolism in adults with prediabetes: an exploratory randomized controlled trial.
Olive leaves are rich in oleuropein, which has been shown to have beneficial effects on dyslipidemia, type 2 diabetes, and obesity. However, we previously found no significant health benefits of olive leaf tea (OLT) on nonobese and nondiabetic individuals. Thus, we performed this study to further explore the health benefits of OLT in individuals with prediabetes and compare the health benefits between low-concentration OLT (LOLT) and OLT. We hypothesized that OLT will have a more pronounced effect on abdominal obesity as well as glucose and lipid metabolism in prediabetic individuals. Individuals between 40 and 70 years of age with a body mass index of 23.0-29.9 kg/m2 and prediabetes status were recruited and randomly assigned to the OLT or the LOLT group. The intervention, which was the consumption of 330 mL of the test beverage 3 times daily during mealtime, lasted for 12 weeks. After the intervention, serum levels of log-transformed triglycerides (P < .05) and low-density lipoprotein cholesterol (P < .01) decreased significantly in the OLT group (n = 28), with the reductions higher in the OLT group than those in the LOLT group (n = 29, log-transformed triglycerides: P = .079, low-density lipoprotein cholesterol: P < .05). Whereas body weight, waist circumference, and insulin levels were not significantly changed in both groups, fasting plasma glucose levels in the OLT group were significantly decreased compared to those in the LOLT group (P < .05). In conclusion, although the effect of OLT on abdominal obesity and glucose metabolism remains unclear, OLT has been found to have lipid-lowering effects.


Genetic and biochemical comparison of 2-aminophenol 1,6-dioxygenase of Pseudomonas pseudoalcaligenes JS45 to meta-cleavage dioxygenases: divergent evolution of 2-aminophenol meta-cleavage pathway.
Nitrobenzene is degraded to pyruvate and acetaldehyde by Pseudomonas pseudoalcaligenes JS45 via a reductive pathway, and by Comamonas sp. JS765 via an oxidative pathway. Although the initial reactions in the degradation of nitrobenzene by the two bacteria are totally different, the lower pathways are similar and converge at the level of 4-oxalocrotonate. In order to further investigate the biochemical properties and reveal the evolutionary relationships between the two lower pathways, the genes encoding the 2-aminophenol 1,6-dioxygenase were cloned and sequenced. 2-Aminophenol 1,6-dioxygenase from P. pseudoalcaligenes JS45 and catechol 2,3-dioxygenase from Comamonas sp. JS765 were able to act on both catechol and 2-aminophenol, but catechol was a suicide substrate of 2-aminophenol 1,6-dioxygenase. The activity of 2-aminophenol 1,6-dioxygenase was restored after removal of catechol and incubation with ascorbate and FeCl(2). Both the alpha-subunit (AmnA) and the beta-subunit (AmnB) of the dioxygenase from P. pseudoalcaligenes JS45 show a high degree of identity to the corresponding subunits of the ring-fission dioxygenase from Pseudomonas sp. AP-3: 67% for the alpha-subunit, and 84% for the beta-subunit. Sequence similarity studies suggest that the beta-subunits of both 2-aminophenol 1,6-dioxygenases are distantly related to homoprotocatechuate 2,3-dioxygenase from Escherichia coli strains W and C and then to catechol 2, 3-dioxygenase from Alcaligenes eutrophus. Four active-site-relevant histidines are conserved in AmnB, but not in AmnA. The lack of conserved histidines indicates the absence of an Fe(2+) binding site in AmnA, which explains the previous observations of only approximately one Fe(2+) per two subunits in the 2-aminophenol 1, 6-dioxygenases from P. pseudoalcaligenes JS45. The 2-aminophenol 1, 6-dioxygenase genes are located upstream of the 2-aminomuconic semialdehyde dehydrogenase gene, and a putative member of the YjgF protein family is upstream of the dioxygenase genes. Transcriptional analysis indicates that the YjgF-like protein, 2-aminophenol 1, 6-dioxygenase, and 2-aminomuconic semialdehyde dehydrogenase are coordinately transcribed. A putative ORF similar to part of the RNA helicase genes is downstream of the dehydrogenase gene. Both the novel organization of the genes and the phylogeny of the dioxygenases and dehydrogenase indicate that the 2-aminophenol pathway in P. pseudoalcaligenes JS45 represents an example of a distant divergent evolution of meta-cleavage pathways.


The suboceanic mantle.
An independent determination of density in the suboceanic lithosphere gives 3.5 to 3.6 grams per cubic centimeter at a depth of about 100 kilometers. This high value implies the existence of an ecologitic facies. A mechanism is proposed in which eclogite fractionation from the underlying, partially molten asthenosphere plays a key role in the creation and the spreading of the rigid, lithospheric plate.


Foot ulceration and its association with mortality in diabetes mellitus: a meta-analysis.
Diabetic foot ulcers portend an almost twofold increase in all-cause mortality compared with diabetes on its own. To investigate the association between diabetic foot ulcers and risk of death. We performed a meta-analysis of all observational studies investigating the association between diabetic foot ulcers and all-cause mortality. Risk ratios and risk differences were pooled in a random-effects model. The I2 statistic was used to quantify heterogeneity between studies. Altogether, we identified 11 studies that reported 84 131 deaths from any cause in 446 916 participants with diabetes during a total of 643 499 person-years of follow-up. The crude event rate for all-cause mortality in individuals with diabetes who did not develop foot ulceration was 22% lower at 181.5 deaths (per 1000 person-years) than in those who developed foot ulcers (230.8 per 1000 person-years). Diabetic foot ulceration was associated with an increased risk of all-cause mortality (pooled relative risk 2.45, 95% CI 1.85-2.85). We did not observe any tangible differences in risk of all-cause mortality from diagnosis in studies reporting a mean duration of follow-up of ≤3 years (relative risk 2.43, 95% CI 2.27-2.61) or >3 years (relative risk 2.26, 95% CI 2.13-2.40) years. Funnel plot inspection revealed no significant publication bias among studies included in this meta-analysis. Our study shows an excess rate of all-cause mortality in people with diabetic foot ulceration when compared to those without foot ulceration. It is imperative that early interventions to prevent foot ulceration and modify cardiovascular disease risk factors are put in place to reduce excess mortality.


Identification in a fish species of two Id (inhibitor of DNA binding/differentiation)-related helix-loop-helix factors expressed in the slow oxidative muscle fibers.
Helix-loop-helix (HLH) proteins related to the inhibitor of DNA binding/differentiation (Id) serve as general antagonists of cell differentiation. They lack a basic DNA-binding domain and are thought to function in a dominant negative manner by sequestering basic HLH (bHLH) transcription factors that are involved in cell determination and differentiation. Four Id-encoding genes have been shown in mammals, they have a distinct pattern of expression suggesting different functions for each member in different cell lineage. In this study we describe the identification and cloning of two trout cDNAs which encode helix-loop-helix proteins showing a high degree of similarity with mammalian Id family members. One cDNA encodes a trout putative Id1 protein (TId1) that is 63% identical to the human Id1 protein over the entire length and 78% identical within the HLH region. The other cDNA encodes a trout putative Id2 protein (TId2) that shows 82% identity to the human Id2 protein and only one change that is conservative over the HLH region. In the 3' untranslated region, TId2 mRNA exhibits 16 nucleotides upstream from the AATAAA site, a palindromic sequence similar to the cytoplasmic polyadenylation element (CPE) which is also present in Id2 and Id3 mRNAs from mammals and in XIdx/XIdI mRNA from Xenopus. In the fish, TId1 and TId2 are expressed in a tissue-specific manner, with slightly different patterns. During myogenesis, TId1 and TId2 are highly expressed in the myotomal musculature of fish embryos and of early alevins but are down-regulated in that of late alevins. In muscle from juveniles and adults, TId1 and TId2 transcripts are abundant in the slow oxidative fibers while they are absent in the fast glycolytic fibers. This expression pattern suggests that Id genes play a role in the regulation of muscle fiber phenotype in addition to controlling early myogenesis. On the whole, the identification of two HLH-Id encoding genes in a major taxonomic group like teleosts, suggests an early divergence of Id genes in vertebrate evolution. The observation that Id transcripts are present selectively in the slow muscle reveals that their expression is more complicated than previously appreciated.


Porin proteins have critical functions in mitochondrial phospholipid metabolism in yeast.
Mitochondrial synthesis of cardiolipin (CL) and phosphatidylethanolamine requires the transport of their precursors, phosphatidic acid and phosphatidylserine, respectively, to the mitochondrial inner membrane. In yeast, the Ups1-Mdm35 and Ups2-Mdm35 complexes transfer phosphatidic acid and phosphatidylserine, respectively, between the mitochondrial outer and inner membranes. Moreover, a Ups1-independent CL accumulation pathway requires several mitochondrial proteins with unknown functions including Mdm31. Here, we identified a mitochondrial porin, Por1, as a protein that interacts with both Mdm31 and Mdm35 in budding yeast (Saccharomyces cerevisiae). Depletion of the porins Por1 and Por2 destabilized Ups1 and Ups2, decreased CL levels by ∼90%, and caused loss of Ups2-dependent phosphatidylethanolamine synthesis, but did not affect Ups2-independent phosphatidylethanolamine synthesis in mitochondria. Por1 mutations that affected its interactions with Mdm31 and Mdm35, but not respiratory growth, also decreased CL levels. Using HeLa cells, we show that mammalian porins also function in mitochondrial CL metabolism. We conclude that yeast porins have specific and critical functions in mitochondrial phospholipid metabolism and that porin-mediated regulation of CL metabolism appears to be evolutionarily conserved.


Association of History of Gestational Diabetes With Long-term Cardiovascular Disease Risk in a Large Prospective Cohort of US Women.
Previous studies identify gestational diabetes (GD) as a risk factor for intermediate markers of cardiovascular disease (CVD) risk; however, few are prospective, evaluate hard CVD end points, or account for shared risk factors including body weight and lifestyle. To prospectively evaluate history of GD in relation to incident CVD risk. The Nurses' Health Study II (NHS II) is an observational cohort study of US female nurses established in 1989, with ongoing follow-up. Biennial questionnaires updated behavioral characteristics, health outcomes, and lifestyle factors. Multivariable Cox models estimated the hazard ratio (HR) and 95% CI for CVD risk. We included 89 479 women who reported at least 1 pregnancy and were free of CVD and cancer at baseline. Follow-up through May 31, 2015, was complete for more than 90% of eligible participants. History of GD was self-reported at baseline (1989) via questionnaire and updated every 2 years. We observed 1161 incident self-reported nonfatal or fatal myocardial infarction or stroke, confirmed via medical records. Participants had a mean (SD) age of 34.9 (4.7) years. Adjusting for age, prepregnancy body mass index, and other covariates, GD vs no GD was associated with subsequent CVD (HR, 1.43; 95% CI, 1.12-1.81). Additional adjustment for weight gain since pregnancy and updated lifestyle factors attenuated the association (HR, 1.29; 95% CI, 1.01-1.65). Classifying GD by progression to T2D in relation to CVD risk indicated a positive association for GD with progression to T2D vs no GD or T2D (HR, 4.02; 95% CI, 1.94-8.31), and an attenuated relationship for GD only (HR, 1.30; 95% CI, 0.99-1.71). Gestational diabetes was positively associated with CVD later in life, although the absolute rate of CVD in this younger cohort of predominantly white women was low. This relationship is possibly mediated in part by subsequent weight gain and lack of healthy lifestyle.


11β-Hydroxysteroid dehydrogenase and the brain: Not (yet) lost in translation.
11-beta-hydroxysteroid dehydrogenases (11β-HSDs) catalyse the conversion of active 11-hydroxy glucocorticoids (cortisol, corticosterone) and their inert 11-keto forms (cortisone, 11-dehydrocorticosterone). They were first reported in the body and brain 70 years ago, but only recently have they become of interest. 11β-HSD2 is a dehydrogenase, potently inactivating glucocorticoids. In the kidney, 11β-HSD2 generates the aldosterone-specificity of intrinsically non-selective mineralocorticoid receptors. 11β-HSD2 also protects the developing foetal brain and body from premature glucocorticoid exposure, which otherwise engenders the programming of neuropsychiatric and cardio-metabolic disease risks. In the adult CNS, 11β-HSD2 is confined to a part of the brain stem where it generates aldosterone-specific central control of salt appetite and perhaps blood pressure. 11β-HSD1 is a reductase, amplifying active glucocorticoid levels within brain cells, notably in the cortex, hippocampus and amygdala, paralleling its metabolic functions in peripheral tissues. 11β-HSD1 is elevated in the ageing rodent and, less certainly, human forebrain. Transgenic models show this rise contributes to age-related cognitive decline, at least in mice. 11β-HSD1 inhibition robustly improves memory in healthy and pathological ageing rodent models and is showing initial promising results in phase II studies of healthy elderly people. Larger trials are needed to confirm and clarify the magnitude of effect and define target populations. The next decade will be crucial in determining how this tale ends - in new treatments or disappointment.


De novo germline mutations of the p53 gene in young children with sarcomas.
Germline p53 mutations are associated with cancer predisposition in Li-Fraumeni families as well as in individuals with component tumors of the syndrome. In the majority of cases these mutations have been shown to be inherited rather than de novo. We screened 59 children with primary bone or soft tissue sarcomas. Germline p53 mutations were identified in 2 patients. Interestingly, analysis revealed that both mutations were de novo. Although the frequency of germline p53 mutations in primary pediatric sarcoma patients is low, there is evidence for the importance of considering pediatric patients for testing for de novo mutations.


[Utility of the PET/CT in vulvar cancer management].
To describe the clinical impact of PET/CT in the management of patients with vulvar cancer. Retrospective analysis of 13 PET/CT studies with (18)F-FDG (6 staging and 7 suspected recurrence) corresponding to 10 patients diagnosed with vulvar cancer by biopsy, with a mean age of 64.5 years. The preoperative PET/CT study was analyzed qualitatively according to the lesion region. Surgical excision was carried out, covering all the suspected areas according to the PET/CT study. This was compared with the histopathologic analysis. Abnormal vulvar PET/CT uptake was found in 9 out of the 13 studies and invasion of adjacent structures in 5 of them (urethra, perineal, vagina). The inguinal-femoral lymph nodes were considered as affected in 3 studies and one pelvic lymph node was also affected. Four of the studies had extralymphatic involvement: 3 in lung and 1 in ischiorectal fossa. The PET/CT showed a 100% sensitivity for the detection of the vulvar lesion in squamous cell carcinomas and 60% in non-squamous cell ones. There was a false positive result for local invasion due to urine contamination. One of the studies with lung metastases was related to a synchronous breast tumor. All the pathological lymph node levels detected in the PET/CT study were confirmed in the histopathology study. No new lesions were identified by surgery. PET/CT changed the therapeutic management in 8/13 studies (61.5%). PET/CT is postulated as a useful imaging test for the management of vulvar cancer, mainly in the identification of nodal metastases. It may affect both surgical planning and clinical management. Larger series are needed to confirm our findings.


Evaluation of sludge from paper recycling as bedding material for broilers.
Several materials have been used as bedding substrates in broiler production. In this work, the sludge from paper recycling was tested for its potential use as litter material and was compared with wood shavings. Moisture content, apparent density, and water-holding capacity were measured and characterized in both materials. Later, 192 male broiler chickens were distributed among 16 experimental pens, 8 of which contained wood shavings as bedding material and 8 of which contained the sludge. Growth rate, consumption, tonic immobility, gait score, breast lesions, foot pad dermatitis, hock burn, tibial dyschondroplasia, and metatarsal thickness were determined in the birds. Although the moisture content of the sludge was high, it decreased strongly after 7 d of drying, reaching lower values than those of wood shavings. In general, few differences were found between the materials in terms of bird performance and welfare and only the incidence of hock burn was higher in the sludge than in the wood shavings. Although further research is needed, sludge from paper recycling is a possible alternative to traditional bedding materials because it achieves most of the requirements for broiler bedding materials and does not show negative effects on the birds.


The origins and early elaboration of projectile technology.
The ability of Homo sapiens to kill prey at a distance is arguably one of the catalysts for our current ecological dominance. Many researchers have suggested its origins lie in the African Middle Stone Age or the European Middle Palaeolithic (∼300-30 thousand years ago), but the perishable components of armatures rarely preserve. Most research on this subject therefore emphasises analysis of armature tip size, shape, and diagnostic impacts or residues. Other lines of evidence have included human skeletal anatomy or analyses of the species composition of faunal assemblages. Projectile Impact Marks (PIMs) on archaeofaunal remains offer an ideal complement to this work, but their potential has been restricted mainly to the later Eurasian zooarchaeological record. A review of current evidence and approaches shows that systematic PIM research could add much to our understanding of early projectile technology, especially in Africa.


Peripheral Mechanisms of Remote Ischemic Conditioning.
Ischemic conditioning induces an endogenous protective mechanism that allows organisms to develop resistance to subsequent insults. The conditioning effect occurs across organs and species. Recently, much attention has been given to remote ischemic limb conditioning due to its non-invasive nature and potential therapeutic applications. While tolerance is induced at the primary injury site (e.g. the heart in cardiac ischemia and the brain in stroke), the site of conditioning application is away from the target organ, suggesting the protective factors are extrinsic in nature rather than intrinsic. This review will focus on the peripheral factors that account for the induction of tolerance. Topics of particular interest are blood flow changes, peripheral neural pathways, humoral factors in circulation, and the peripheral immune system. This review will also discuss how conditioning may negatively affect metabolically compromised conditions, its optimal dose, and window for therapy development.


Current and emerging models of residential psychiatric treatment, with special reference to the California situation.
The author reviews the steps that have led to the progressive deemphasis of psychiatric hospitalization in California and surveys the empirical basis for rejecting the usefulness of hospitalization. He discusses the four alternative residential models that have emerged in California as substitutes for state mental hospitals--general hospital psychiatric units, board and care homes, private psychiatric facilities available through vendor contracts, and convalescent hospitals. The author also touches briefly upon some important problems, including the possible fate of public general hospital psychiatric units, community mental health services, and the commitment law in California.


The Effects of Selective Muscle Weakness on Muscle Coordination in the Human Arm.
Despite the fundamental importance of muscle coordination in daily life, it is currently unclear how muscle coordination adapts when the musculoskeletal system is perturbed. In this study, we quantified the impact of selective muscle weakness on several metrics of muscle coordination. Seven healthy subjects performed 2D and 3D isometric force target matches, while electromyographic (EMG) signals were recorded from 13 elbow and shoulder muscles. Subsequently, muscle weakness was induced by a motor point block of brachialis muscle. Postblock subjects repeated the force generation tasks. We quantified muscle coordination pre- and postblock using three metrics: tuning curve preferred direction, tuning curve area, and motor modules analysis via nonnegative matrix factorization. For most muscles, the tuning direction for the 2D protocol was not substantially altered postblock, while tuning areas changed more drastically. Typically, five motor modules were identified from the 3D task, and four motor modules were identified in the 2D task; this result held across both pre- and postblock conditions. The composition of one or two motor modules, ones that involved mainly the activation of shoulder muscles, was altered postblock. Our results demonstrate that selective muscle weakness can induce nonintuitive alternations in muscle coordination in the mechanically redundant human arm.


[Mouse cell line with stable inheritance of colchicine resistance].
A new mouse cell line B-82CH(R)-9 is described, which is 25-fold more resistant to the cytotoxic action of colchicine than the known lines. The drug resistance of this cell line originates from the decreased plasmic membrane permeability. This follows from several facts: 1) 3H-colchicine uptake by intact resistant cells is decreased 5-10-fold; 2) the binding of labeled colchicine by extracts of resistant cells is unchanged; 3) colchicine resistant cells are cross-resistant to the drugs which are not active in binding the microtubular protein tubulin: the uptake of 3H-puromycin and 3H-cytochalasin B is decreased 2.1 and 2.5-fold, respectively. Unlike colchicine resistant mouse cell lines obtained earlier, the drug resistance of B-82CH(R)-9 cells is stable. After cultivation without a selective agent for 3 and 6 months the level of colchicine resistance remained unchanged.


Pediatric Logistic Organ Dysfunction-2 (Pelod-2) score as a model for predicting mortality in pediatric burn injury.
Multiple organ dysfunction syndrome (MODS) is an important cause of mortality in burn injury. Pediatric Organ Logistic Dysfunction (PELOD)-2 score as a descriptive scoring system for organ dysfunction has been highly predictive of mortality in children with suspected infection, but its usefulness for burn patients is unknown. All pediatric burn patients hospitalized in Cipto Mangunkusumo Hospital (CMH) in Jakarta, Indonesia, from January 2012 to January 2017 were studied. Gender, age, nutritional status, burn characteristics, total body surface area burned (%TBSA), depth of burn, inhalation injury, time interval to resuscitation and surgery, day one ABSI and PELOD-2 score, and mortality as outcome were recorded. Bivariate and multivariate analysis logistic regressions were done to generate a mortality prediction model. Mortality rate among subjects was 20.3%. Bivariate analysis showed that extensive %TBSA, depth of burn, presence of inhalation injury, PELOD-2 score and ABSI score in pediatric burn patients were significantly associated with mortality (p<0.001). In multivariate analysis, only PELOD-2 score was independently associated with mortality. PELOD-2 score mortality prediction rate was far lower than actual mortality. Mortality rate by the new model was close to the actual mortality rate. Our new combined model could be used to calculate probability of death based on day 1 PELOD-2 score in pediatric burn patients.


The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis.
The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene-environment interactions (GEI). Genetic and environmental risk factors are being identified with increasing frequency, yet their very number vastly increases the scope of possible GEI, making it difficult to identify them with certainty. Accumulating evidence suggests a dysregulated complement pathway among the pathogenic processes of schizophrenia. The complement pathway mediates innate and acquired immunity, and its activation drives the removal of damaged cells, autoantigens and environmentally derived antigens. Abnormalities in complement functions occur in many infectious and autoimmune disorders that have been linked to schizophrenia. Many older reports indicate altered serum complement activity in schizophrenia, though the data are inconclusive. Compellingly, recent genome-wide association studies suggest repeat polymorphisms incorporating the complement 4A (C4A) and 4B (C4B) genes as risk factors for schizophrenia. The C4A/C4B genetic associations have re-ignited interest not only in inflammation-related models for schizophrenia pathogenesis, but also in neurodevelopmental theories, because rodent models indicate a role for complement proteins in synaptic pruning and neurodevelopment. Thus, the complement system could be used as one of the 'staging posts' for a variety of focused studies of schizophrenia pathogenesis. They include GEI studies of the C4A/C4B repeat polymorphisms in relation to inflammation-related or infectious processes, animal model studies and tests of hypotheses linked to autoimmune diseases that can co-segregate with schizophrenia. If they can be replicated, such studies would vastly improve our understanding of pathogenic processes in schizophrenia through GEI analyses and open new avenues for therapy.


The impact of tobacco on lung health in China.
China has the largest production and consumption of tobacco worldwide. It has witnessed a dramatic increase in tobacco consumption over the past two decades, with more than 34.8 million cartons of cigarettes being produced and 34.7 million sold annually. Approximately 67% of males and 4% of females aged over 15 years in China are smokers, and the total of over 320 million Chinese smokers represents about one-third of all smokers worldwide. The continuous, rapid increase in the number of Chinese smokers is largely due to teenagers taking up smoking. Among teenagers aged 15-19 years, 18% of men and 0.28% of women (making a total of 9 million teenagers) are smokers. The prevalence of passive smoking is very high at 53.5%, about 0.3 billion people aged above 15 years were affected. The average daily consumption of tobacco per person in China rose from one cigarette in 1952 to 10 cigarettes in 1990, a rate similar to that of the USA 40 years earlier. It seems inevitable that China will witness a substantial increase in mortality following this increase in smoking. Based on current smoking rates, the predicted deaths attributed to smoking in China will rise to 3 million in 2050. If the current smoking pattern in China remains unchanged, 100 million men now under 30 years will die from smoking-related diseases. The respiratory system is harmed most by tobacco smoke. Over two-thirds of all deaths related to smoking in China are attributed to chronic obstructive pulmonary disease (COPD), lung cancer and pulmonary tuberculosis. The morbidity of COPD alone in China is estimated at over 3%, or 25 million people, of whom 72% were smokers. The Chinese government consistently supports smoking control and advocates smoking abstinence via laws to restrain the sale and advertising of tobacco. These actions have been successful in some aspects, and in particular, more people are aware that 'cigarette smoking is harmful to health'. In future, the emphasis of smoking control should be directed at restraining teenagers and adolescents from smoking. Cigarette smoking has already caused significant ill-health to the Chinese population with over 1 million people dying each year of various disorders caused by smoking. However, the peak of smoking-induced diseases is still to come and therefore, it is very important to strengthen anti-smoking measures so as to have a far-reaching effect on the future health of the Chinese population.


Re-engineering multicloning sites for function and convenience.
Multicloning sites (MCSs) in standard expression vectors are widely used and thought to be benign, non-interacting elements that exist for mere convenience. However, MCSs impose a necessary distance between promoter elements and genes of interest. As a result, the choice of cloning site defines the genetic context and may introduce significant mRNA secondary structure in the 5'-untranslated region leading to strong translation inhibition. Here, we demonstrate the first performance-based assessment of MCSs in yeast, showing that commonly used MCSs can induce dramatic reductions in protein expression, and that this inhibition is highly promoter and gene dependent. In response, we develop and apply a novel predictive model of structure-based translation inhibition to design improved MCSs for significantly higher and more consistent protein expression. In doing so, we were able to minimize the inhibitory effects of MCSs with the yeast TEF, CYC and GPD promoters. These results highlight the non-interchangeable nature of biological parts and represent the first complete, global redesign of a genetic circuit of such widespread importance as a multicloning site. The improved translational control offered by these designed MCSs is paramount to obtaining high titers of heterologous proteins in eukaryotes and to enabling precise control of genetic circuits.