Factors associated with diabetic retinopathy screening and regular eye checkup practice among diabetic patients attending Felege Hiwot Specialized Hospital.
To identify associated factors of diabetic retinopathy (DR) screening and ey e check-up practice among diabetes mellitus (DM) patients attending Felege Hiwot Specialized Hospital. An institution-based cross-sectional study was applied from October 4, 2019 to January 12, 2020 at Felege Hiwot Specialized Hospital. A systematic random sampling technique was used to recruit participants and an interviewer-administered questionnaire was employed to collect the data. The collected data were entered into Epi Info version 7 and transposed to SPSS version 24 for statistical analysis. Descriptive statistics were executed and associated factors were identified using binary logistic regression. The strength of association between the independent and the outcome variable was determined using an adjusted odds ratio (AOR) with 95% confidence interval (CI). Four hundred and six participants partake with a response rate of 95.7% and a mean age of 47±11.5y. The magnitude of DR screening was 308 (75.9%, 95%CI: 71.5%, 79.8%). Higher educational level (AOR=3.25; 95%CI: 1.40, 8.78), good knowledge of DR (AOR=2.50; 95%CI: 1.55, 4.46), and family history of DM (AOR=2.15; 95%CI: 1.41, 3.85) were significantly associated with DR screening. On the other side, rural residence [AOR=3.11 (1.89, 5.02)] and undesirable attitudes toward DR [AOR=5.65 (3.14, 8.76)] were significantly associated with poor regular eye checkup practice. Most of the participants are screened for DR. Higher education, family history, and good knowledge are associated with DR screening. In addition, rural residence and undesirable attitudes toward DR are associated with regular eye checkup practice.


Antiparasitic agents.
Parasitic diseases predominantly affect the developing world because of poor sanitation, poor living conditions, and lack of medical care. The relative insulation of the developed countries has been protective until recently, when several factors have made populations worldwide potentially at risk of infection by any transmissible agent. Emigration, forced migration of refugees, increasing and rapid world travel, and increased susceptibility of immunocompromised populations, have been methods by which parasites, and quite often their associated vectors, have been imported into and have taken hold in regions previously unaffected. Health officials, clinicians, blood banks and pathologists who have not routinely encountered such diseases are, however, at the forefront in efforts to control these diseases. With regard to antiparasitic agents, the emphasis at this meeting was placed on their current increasing importance. Accompanying the greater incidence and disease spread are the withdrawal of prevention measures and vaccines, the resistance to chemotherapeutic agents and lack of awareness and vigilance in medical communities to the threats of resurgent and emerging diseases. A snapshot of these diseases was presented at the symposia. This report highlights the discovery, re-emergence, epidemiology, transmission, diagnosis and therapy of parasitic diseases. A common theme to the presentations was the emergence or re-emergence of organisms previously thought to be under control. Modern biotechnology and biochemical methods are being applied to the problems of causative agent identification and characterization. With better surveillance methods, no doubt the detection of more diseases will continue. No tremendous breakthroughs in parasite prevention, chemotherapy, or successes of antiparasitic agents in clinical trials were reported and are unlikely to be forthcoming in the near future unless greater changes are made in the research community, including the pharmaceutical industry. It was of note that no symposia were devoted wholly to parasites as such, but were directed towards the exposition of emerging pathogens, of which parasites comprise only a segment of the spectrum of causative organisms.


In vitro transcription and immobilized template analysis of preinitiation complexes.
In the study of gene regulation, it is often necessary to employ functional assays that investigate the action or mechanism of specific promoters or enhancer-binding factors and their role in transcription by RNA polymerase II. Although many assays measure the transcription of a gene under the control of an endogenous or model activator in vivo, it is often useful to recreate transcription in vitro in order to study specific regulatory mechanisms. In this unit, protocols are presented that will allow the investigator to perform in vitro transcription using preinitiation complexes assembled from cellular extracts on either naked DNA or chromatin templates.


Long-term cohort study comparing medical (oxcarbazepine) and surgical management of intractable trigeminal neuralgia.
Trigeminal neuralgia is a recurrent severe shooting neuropathic pain which can be managed both pharmacologically and surgically. However, there are no prospective data that compare these two therapeutic strategies. This study therefore aimed to assess long-term outcome in patients with intractable trigeminal neuralgia treated with oxcarbazepine and later with surgery. Fifteen patients (11 females) with trigeminal neuralgia intractable to available drugs (carbamazepine, phenytoin and baclofen), were prospectively followed for 13 years (1986-1999) with a total follow up time from onset of disease of 16 +/- 6 years (mean +/- SD), range 8-30 years. All patients were contacted in 1999 and 12 replied, two had died and one had last replied in 1996. Patients were first treated with oxcarbazepine 1200 +/- 600 mg daily dosage (mean +/- SD) and subsequently with surgery of their choice. The outcome measures used were: McGill Pain Questionnaire, Hospital Anxiety and Depression Scale, patient satisfaction questionnaire and clinicians' global evaluation. Pain control was initially achieved in all patients and oxcarbazepine was used continuously or intermittently for 4.0 +/- 3 years (mean +/- SD). Thirteen patients experienced some mild side effects and a dose-dependent hyponatraemia was noted. Subsequently, 12 patients required surgery (five microvascular decompressions and seven surgery at the level of the Gasserian ganglion) to control their pain and were followed up for 4.3 +/- 1.7 years post surgery (mean +/- SD). Three patients required repeat surgery to control their pain, which was successful in two. A further two patients continued with low dose medication post initially successful surgery. Three patients reported numbness and one hearing loss after surgery. Kaplan Meier analysis 3 years after oxcarbazepine use and then 3 years after surgery showed that the mean time for recurrence of pain after oxcarbazepine treatment was 10 months whilst for surgery it was 28 months (P<0.0001). Pain free periods and types of complications post surgery varied and depended on the type of surgery performed. Due to the small numbers, it was not possible to analyse the different types of surgical procedures individually. Outcomes after any type of surgery were better on all evaluations and eight patients felt that they should have had surgery earlier. Oxcarbazepine is a potent antineuralgic drug with very good acceptability and tolerability. However, its effectiveness was rather short term necessitating surgical intervention. As surgery was associated with better outcome, patients may therefore benefit from having surgery earlier rather than later in the disease process in order to improve quality of life, freedom from medication and the need for regular follow up. Surgery does not provide pain relief for all patients. This is the first study that has compared outcome in a group of patients who have had both pharmacological and surgical treatments. As these data cannot be extrapolated to other antineuralgic drugs, similar comparative studies would be appropriate.


[Prevalence and morphology of pineal cysts discovered at pituitary MRI: review of 1844 examinations].
To evaluate the frequency, morphology and clinical long term evolution of pineal cysts depicted on MRI. one thousand eight hundred and forty four (1 532 women and 126 men) MRI examinations were retrospectively reviewed. Coronal and sagittal spin echo T1 weighted sequences without and with gadolinium injection were performed, completed with spin echo T2 weighted images when a cystic sellar lesion was suspected. A pineal cyst was diagnosed as a rounded well defined lesion, with fluid signal in an enlarged pineal gland. Follow-up examinations were performed to evaluate the efficacy of the treatment of the sellar lesion. Twenty one epiphyseal cysts (1.27%) were diagnosed in 20 women (1.31%) and one man (0.79%). Their size was 1,2 +/- 0,4 cm (0,3 to 2 cm). They were asymptomatic. In 10 patients, follow-up MRI examinations did not show any change in size. During the clinical follow-up, these twenty-one patients remained asymptomatic (6 months to 5 years). The incidental detection of a pineal cyst at MRI is not exceptional. This lesion's pattern appears characteristic and their reputation of benignity is confirmed in our study.


Identifying the predictors of needling after XEN gel implant.
To identify factors associated with probability of needling after XEN implant. Analysis of data from prospective case series of patients with standalone XEN implant or combined XEN + cataract. Primary outcome was to determine whether postoperative day 1 and week 1 intraocular pressure (IOP), type of glaucoma, and glaucoma severity affected probability and number of needling interventions required. A total of 149 eyes of 113 patients were included in the analysis. In the XEN alone group, mean IOP at day 1 and week 1 was 9.70 ± 5.43 and 10.33 ± 4.41 mmHg, respectively. Eyes with lower IOP on day 1 were less likely to require needling (Odds ratio; OR, 1.14; 95% CI, 1.02-1.28; p = 0.02). A similar association (OR, 1.15; 95% CI, 1.06-1.26; p = 0.001) was observed between day 1 IOP in and number of needling interventions. In the XEN + cataract group, mean IOPs at day 1 and week 1 were 13.75 ± 7.52 and 11.81 ± 5.36 mmHg, respectively. No significant association was noted between early postoperative IOP and probability or number of needling in this group. With IOP > 20 mmHg the probability of needling was ~ 80%. This number decreased to 35% if day 1 IOP was < 10 mmHg. Postoperative day 1 IOP is a predictor for needling in patients undergoing standalone XEN implantation. These results suggest that surgeons should not wait too long to intervene via needling if IOP in the early postoperative period is in the high teens or above. Type or severity of glaucoma did not influence the probability of needling or number of needling interventions required.


Macroinvertebrates at the source: flow duration and seasonality drive biodiversity and trait composition in rheocrene springs of the Western Allegheny Plateau, USA.
Documenting flow regimes and the ecology of source headwater streams has gained considerable attention for scientific and regulatory purposes. These streams do not appear on standard maps, and local physiographic and climatologic conditions can control their origins. We investigated macroinvertebrate assemblages seasonally and in relation to flow duration, catchment and habitat variables within 14 source headwaters (< 1 ha) in the Western Allegheny Plateau over a 19-month period. We classified 6 perennial (P) and 8 intermittent (I) streams directly with continuous flow data loggers. Several biological and trait-based metrics could distinguish flow class, but few instream physical measures could. Macroinvertebrate metrics and assemblage dispersion varied seasonally and responded significantly along a gradient of total flow duration. Separate indicator species analyses generated 22 genera and 15 families with significant affinities to P streams. Richness of P-indicator taxa was also strongly correlated with flow duration gradients, and we estimated a total flow duration changepoint at 77% (3 indicator families) followed by a sharp increase in richness. Two rapid field-based flow duration methods (NC Stream Identification index and OH Headwater Habitat Evaluation index) could distinguish upstream ephemeral reaches from P and I reaches, but misclassified P as I more frequently. Our findings highlight that diverse coldwater macroinvertebrate assemblages inhabited extremely small, low-discharge springs in the region, and responded with flow duration. These source headwater habitats are susceptible to human disturbance and should be monitored as is routinely done in larger lotic systems.


Developing mental health services in response to research evidence.
Over the last thirty to forty years, psychiatric care in England has relocated from hospital-based settings to community mental health teams (CMHTs) and supported accommodation. Since the 1980s, two forms of intensive home based treatment have evolved in addition to CMHTS, assertive community treatment (ACT) and crisis resolution teams (CRTs). On the basis of evidence for their efficacy in the US and other countries, they have been implemented across England through the Government's National Service Framework for Mental Health. This paper describes this evidence and the first UK studies that were carried out to evaluate these newly implemented services. Descriptions of the evaluations of ACT and CRTs in the inner London boroughs of Camden and Islington. The implementation of CRTs in North London were associated with reduced use of inpatient services, but the ACT teams were not. Both types of team were associated with greater patient satisfaction with services and the ACTs were better able to engage patients than CMHTs. The authors comment on the implications of the findings for service planners in terms of the difficulties in implementing innovative approaches based on the best available evidence when it originates outside the local context.


Mutations in human gonadotropin and gonadotropin-receptor genes.
This short review provides an update on the new information that has become available in the recent years about mutations and polymorphisms in the genes for gonadotropins and their receptors. Combining the types and locations of the mutations, their phenotypic effects, and the recently emerged information about the crystal structure of these molecules is providing us with increasingly detailed picture about the structure-function relationships of gonadotropin action.


Postoperative Serum CEA Level is a More Significant Prognostic Factor than Post/Preoperative Serum CEA Ratio in Non-small Cell Cancer Patients.
In non-small cell lung cancer (NSCLC) patients with preoperative high serum carcinoembryonic antigen (CEA) level, patients with a persistently high serum CEA level after surgery have been reported to have a poor prognosis. In addition, in other cancers, the post/preoperative serum CEA ratio has been reported as a useful parameter. We enrolled 123 NSCLC patients with preoperative high CEA levels (≥ 5 ng/mL) who underwent curative surgery between 2004 and 2011. Prognostic significance of postoperative serum CEA level and the CEA ratio was examined. The 5-year survival of patients with persistently high serum CEA level after surgery was poor. On the other hand, patients with normal postoperative serum CEA levels had significant favorable prognosis. The patients with CEA ratio>1 had poor prognosis, however the number was only 7 (5.7%). The 5-year survival rates of patients with other subgroup based on the CEA ratio (0.5 ≥ CEA ratio and 0.5 ≤ CEA ratio ≤ 1) was similar. Multivariate analysis revealed prognostic significance for the postoperative serum CEA level but not the CEA ratio. For NSCLC patients with preoperative high serum CEA level, their postoperative serum CEA levels is a more significant prognostic factor than the post/preoperative serum CEA ratio.


The effect of suture removal on postkeratoplasty astigmatism.
I followed up for a minimum of six months 439 eyes that had undergone corneal transplantation using a suturing technique consisting of eight interrupted 10-0 and a single, continuous, 16-bite 11-0 nylon suture. All sutures were removed from 188 eyes an average of 20 months after surgery. After suture removal, 64 corneas had an increase of astigmatism greater than 0.5 diopter, 79 eyes showed a decrease in astigmatism greater than 0.5 diopter, and 42 corneas had no change in astigmatism. The mean astigmatism before suture removal was 3.7 diopters, and the mean astigmatism after suture removal was 3.5 diopters. There was no apparent difference in postkeratoplasty astigmatism with donor corneal diameters 0.25 to 0.75 mm greater in diameter than the recipient diameters, or with different host diseases. The longer the sutures were left in place after surgery, the smaller the quantitative change in astigmatism after suture removal. The complications of this technique were no different from other currently used suture techniques.


Influence of stance width and toe direction on medial knee contact force during bodyweight squats.
Squats are frequently performed to strengthen the quadriceps (Quad) and gluteus maximus (GM) in sports and clinical fields. Since the squat itself produces a large knee contact force, clarifying the relationship between the squat techniques and the knee contact force is important. However, the influence of different squat techniques on the medial knee contact force (KCFmed), which would result in knee disease, remains unclear. This study aimed to investigate the influence of various squat techniques on KCFmed during bodyweight squats. Since muscle strengthening by the squat is inevitable, we additionally aimed to explore the effect of a different squat technique on the quadriceps (Quad) and gluteus maximus (GM) forces. Twelve healthy adults performed squats with different stance widths (narrow stance, NS; middle stance, MS; and wide stance, WS) and different toe directions (0° of forefoot abduction - NEUT and 30°forefoot abduction - OUT). The KCFmed, Quad force, and GM force were computed using a musculoskeletal model with marker trajectories and ground reaction forces. The KCFmed in NS was significantly larger than that in MS and WS, and KCFmed in OUT was significantly larger than that in NEUT. The Quad force in OUT was significantly larger than that in the NEUT, and the GM force significantly became larger as the stance width became narrower. These findings suggest that squats in MS and NEUT may be suitable for reducing KCFmed while maintaining the Quad and GM forces.


Human papilloma virus (HPV) and prostate cancer (PCa): The potential role of HPV gene expression and selected cellular MiRNAs in PCa development.
Prostate cancer (PCa) is one of the most common and health-threatening cancers in men worldwide. The human papillomavirus (HPV) is considered one of the organisms with the potential to be involved in the progression of this cancer. In the present study, we evaluated the association between the expression levels of HPV genes with the expression of selected cellular miRNAs (miR-19a, miR-21, miR-23b, miR-34a, miR-150-5p, and miR-155) and their targets genes (P53, Rb, c-Myc, TIMP-1, MMP-2, MMP-9, PDCD4, Bcl-2, and Survivin) in PCa tissue samples. HPV detection and genotyping were performed on the tissues of 112 PCa patients and 39 healthy individuals. The expression profile of miRNA was evaluated by SYBR Green-based real-time PCR. As well Human Survivin ELISA Kit was utilized to determine the concentrations of Retinoblastoma, P53, survivin, Bcl-2, c-Myc, TIMP-1, MMP-2, MMP-9, and PDCD4 in the prostate tissues. According to our findings, HPV genome was detected in 28.7% (21/73) of PCa tissue specimens and 17.94% (7/39) control samples. There was no significant association between the presence of HPV infection with PCa (OR = 2.01, 95%CI = 0.8-5.68, P = 0.102). We found that mean expression level of miR-19a (3.7 ± 4.3, p-value: 0.0007), and -21 (2.5 ± 2.8, p-value<0.0001) were significantly higher and miR-23b (-2.14 ± 3.08, p-value: 0.003) and -34a (-3.12 ± 3.28, p-value: 0.0001) levels were significantly lower in PCa tissue samples than in control tissue samples. Present research indicated that HPV positive PCa has a distinct miRNA profile compared with HPV negative PCa.


Non-peptide antagonists, CP-96,345 and RP 67580, distinguish species variants in tachykinin NK1 receptors.
1. The potency of the non-peptide antagonists CP-96,345 and RP 67580 on NK1 receptor-stimulated [3H]-inositol phosphate accumulation in cell lines or tissue from three different species has been examined. 2. We have used: UC11 cells, derived from a human astrocytoma, and rat LRM55 glial cells, both of which express large numbers of functional NK1 receptors, and the well characterized guinea-pig ileum which expresses both NK1 and NK3 receptors. 3. RP 67580 has an approximately 25 fold lower affinity for NK1 receptors in human UC11 cells (Kd = 194 nM) than in rat LRM55 cells (Kd = 7.9 nM), in contrast CP-96,345 has an approximately 200 fold lower affinity in rat LRM55 cells (Kd = 210 nM) relative to human UC11 cells (Kd = 0.99 nM). The pharmacological profile of CP-96,345 and RP 67580 in guinea-pig ileum was similar to that observed in human UC11 cells. 4. In conclusion, we have demonstrated that previously reported species differences in binding affinities for the non-peptide NK1 antagonists, CP-96,345 and RP 67580, are also observed in inhibition of NK1 receptor stimulated hydrolysis of inositol phospholipids.


Head and Neck Squamous Cell Carcinoma in Iran: Clinico-Pathological and Treatment-Related Factors Influencing Survival.
Evidences about survival of the patients with head and neck squamous cell carsinoma (HNSCC) have been scant in our region. The aim of current study was to determine clinico-pathological and treatment-related factors, influencing outcome of these patients. We have reviewed all patients with a new diagnosis of HNSCC admitted between 2008 and 2014 in "Jorjani Cancer Center", Tehran, Iran. Overall survival (OS) and event free survival (EFS) of the patients, and their relation with demographic and clinico-pathological factors have been analyzed. Among 119 included patients, 90 were male and 29 were female with mean age of 58 years. Larynx was the most common primary tumor site (55% of all patients). With a median follow-up period of 28 months, OS and EFS of the study patients was 61.2% and 52.4%, respectively. Tumor stage was the only parameter has significantly influenced the patients' OS. Patients with normal BMIs had significantly higher mean EFS compared with patients with bellow or above normal BMIs. Surgical treatment modalities have resulted in the same prognosis as non-surgical approaches. Our study seems to be the first that investigated outcome of Iranian patients with head and neck cancer and its influencing factors.


Clinical Use of A Priori Knowledge of Organ-At-Risk Sparing During Radiation Therapy Treatment for Oropharyngeal Cancer: Dosimetric and Patient Reported Outcome Improvements.
This study aimed to prospectively assess dosimetric and clinical effects of treatment planners having a priori knowledge of the maximum achievable dose sparing for organs at risk (OARs) for patients with oropharynx cancer receiving intensity modulated radiation therapy (RT). We examined patients with oropharynx cancer who were treated in prospective clinical trials between February 2012 and April 2019 at our institution. A tool generating estimates of maximum achievable dose sparing for OARs (feasibility dose-volume histogram [FDVH]) was used clinically starting July 2016. Patients were divided into 2 cohorts: Before (ie, baseline) and after (ie, FDVH-guided) FDVH. Doses received by various OARs were compared with those estimated to be achievable per FDVH, and that difference was defined as the excess of feasible dose (EFD). Patient-reported outcome (PRO) questionnaires were completed at 3, 6, and 12 months after treatment. The baseline and FDVH-guided cohorts were compared in terms of EFD, plan quality metrics, and post-RT PRO assessments. A total of 139 patients were included in the analysis (60 in the baseline cohort, 79 in the FDVH-guided cohort). The FDVH-guided cohort had lower EFD to the contralateral parotid by 4.1 Gy, the ipsilateral parotid by 10.6 Gy, the larynx by 4.3 Gy, the oral cavity by 1.5 Gy, and the contralateral submandibular gland by 0.4 Gy. Plan quality metrics were similar between the cohorts. Less variation of EFD was seen in the FDVH-guided cohort for the parotid glands and contralateral submandibular gland (P < .05). The average post-RT PROs were better in the FVHD cohort versus baseline (particularly at the 6-month timepoint for dry mouth frequency, sticky saliva, meal enjoyment, severity of pain, and Eating Assessment Tool 10 composite [swallowing]; P < .05). Use of FDVH was associated with improved and less variable OAR sparing for clinically delivered plans. FDVH-guided patients had improved PROs compared with baseline with a variety of outcomes significantly improved at 6 months after treatment.


Preliminary study on forgery identification of Hetian Jade with Instrumental Neutron Activation Analysis.
In this study, Instrumental Neutron Activation Analysis (INAA) was applied to study the elemental information of geological samples with the assistance of chemometric techniques. Samples of genuine Hetian Jade from Xijiang Province of China, counterfeit jade samples purchased at the neighborhood market, and granitoid samples from the same geographic location of genuine Hetian Jade were analyzed using INAA. The preliminary study indicates that INAA, with the help of principal component analysis (PCA), can be applied to obtain the multi-elemental concentrations of geological samples with high sensitivity, thereby effectively differentiating genuine Hetian Jade from counterfeit ones.


Longitudinal treatment patterns in patients recently diagnosed with type 2 diabetes mellitus in Catalonia.
To investigate initial and subsequent treatments prescribed to newly diagnosed type 2 diabetes mellitus (T2DM) patients. Data from SIDIAP (Information System for Research in Primary Care) including all recorded incident T2DM patients in primary care between 2015 and 2020. We used descriptive statistics and different graphical techniques to describe the most frequent longitudinal patterns. A total of 86,854 patients were included. 78.3 % of the patients began treatment with a single metformin medication and 21.7 % began with a combination therapy (CT). Metformin was the most frequent treatment as first and third-line therapy, while the CT of metformin with DPP4i or sulfonylurea was more prevalent as second-line. Most common first to third-line pattern was initial metformin for 15 months, adding a second antidiabetic in the second line, staying in CT for 6 months, and switching back to single metformin. Treatment patterns varied depending on HbA1c levels, with higher levels (>8 %) being associated with changes to CT and lower levels with switches to monotherapy or temporary discontinuation. The study described in detail the different treatment patterns in incident T2DM patients in Catalonia, its adherence to the guidelines, and how the changes are associated to the HbA1c dynamics.


Reconstruction and repair, using mini-plate and bone graft for persons living with HIV with giant cell tumor of long bone: retrospective analysis of a single-center experience.
To evaluate the effect of reconstruction and repair, using a mini-plate and bone graft for HIV -positive patients with giant cell tumor of long bone. We conducted a retrospective analysis of 12 HIV positive patients with giant cell tumor of long bone. A non-HIV-positive cohort of patients, matched for age, sex, and disease type, was selected as the control group. From June 2012 to August 2020, curettage by ultrasonic scalpel was performed in all patients, combined with min- plate and bone graft treatment. All patients were followed- up for 18 to 60 months. Limb function was evaluated, using the MSTS93 scoring system, and any examples of postoperative recurrence, distant metastasis, complications, MSTS93 score, and fracture prognosis were recorded. The mean age of HIV group was 43.5 years. The ratio of men to women was 11: 1. In all cases the histopathological diagnosis was clear, except the patients with primary malignant giant cell tumor of bone, including five, three, two, and two cases in the proximal tibia, distal femur, distal tibia, and talus, respectively. Following their surgery, all patients were followed up with an average of 31.24 ± 11.84 months. No local recurrence or pulmonary metastases were observed. Post-surgery, all the 12 patients showed good bone morphologic repair and reconstruction, good bone healing, good joint function, and no pathological fractures around their lesion. In the HIV group, one case of giant cell tumor in the proximal tibia showed mild articular surface collapse and mild valgus deformity of the knee joint but retained good joint function. The MSTS scores of excellent or good in the two groups comprised 83.3%, thus, there was no significant difference between them (P > 0.05). Compared with preoperatively, the MSTS scores in the HIV group were significantly improved, ranging from 7 to 11 points preoperatively to 24 to 27 points postoperatively; this difference was statistically significant (P < 0.05). Reconstruction and repair, using a mini-plate and bone graft for HIV -positive patients with giant cell tumor of long bone can achieve satisfactory results. The mini- plate requires little space and is flexible during reconstruction and fixation, significantly reducing complications such as surgical site infection, as well as preserving joint function and avoiding amputation; therefore, it is a safe and effective treatment method.


Drug metabolic enzyme genotype-phenotype discrepancy: High phenoconversion rate in patients treated with antidepressants.
Cytochromes from the P450 family (CYP) play a central role in the primary metabolism of frequently prescribed antidepressants, potentially affecting their efficacy and tolerance. There are however important differences in the drug metabolic capacities of each individual resulting from a combination of intrinsic and environmental factors. This variability can present an important risk for patients and increases the difficulty of drug prescription in clinical practice. Pharmacogenetic studies have uncovered a number of alleles defining the intrinsic metabolizer status, however, additional factors affecting cytochrome activity can modify this activity and result in a phenoconversion. The present study investigates the discrepancy between the genetically predicted and actually measured activities for the six most important liver cytochromes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) in a cohort of patients under antidepressant treatment, previously shown to have a high proportion of patients with low metabolizing activities. We now performed the genetic characterization of this cohort to determine the extent of the genetic versus environmental contribution in these decreased activities. For all enzyme tested, we observed an important rate of phenoconversion, affecting between 33 % and 65 % of the patients, as well as a significant (p < 1E-06) global reduction in the effective but not predicted activities of CYP2D6, CYP2C9 and CYP2C19 compared to the general population. Our results highlight the advantages of phenotyping versus genotyping as well as the increased risk of treatment failure or adverse effect occurrence in a polymedicated population.


The stimulation of arachidonic acid metabolism in human platelets by hydrodynamic stresses.
Even though shear-induced platelet activation and aggregation have been studied for about 20 years, there remains some controversy concerning the arachidonic acid metabolites formed during stress activation and the role of thromboxane A2 in shear-induced platelet aggregation. In this study, platelets were labelled with [1-14C]arachidonic acid to follow the metabolism of arachidonic acid in stimulated platelets using HPLC and scintillation counting. Platelets activated by thrombin formed principally thromboxane A2, 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE). In contrast, for platelets activated by shear--though arachidonic acid metabolism was stimulated--only 12-HETE was formed and essentially no cyclooxygenase metabolites were detected. This indicates that physical forces may initiate a different pathway for eicosanoid metabolism than most commonly used chemical stimuli and perhaps also implies that regulation of the cyclooxygenase activity may be a secondary level of regulation in eicosanoid metabolism.


The 75-kD tumour necrosis factor (TNF) receptor is specifically up-regulated in monocytes during Q fever endocarditis.
Q fever is an infectious disease caused by Coxiella burnetii, an obligate intracellular microorganism that inhabits monocytes/macrophages. The dysregulated production of TNF-alpha in Q fever endocarditis has been associated with defective killing of C. burnetii by patient monocytes. As soluble receptors for TNF-alpha (TNF-R55 and TNF-R75) regulate TNF-alpha activity, we investigated their release by monocytes in Q fever. Spontaneous and C. burnetii-stimulated release of TNF-R75, but not of TNF-R55, was up-regulated in patients with ongoing endocarditis compared with controls. The increase in TNF-R75 release was related to the activity of Q fever endocarditis, since TNF-R75 release was similar in patients with cured endocarditis and controls. While spontaneous release of TNF-R75 by monocytes from patients with ongoing Q fever endocarditis occurred without changes in its membrane expression, C. burnetii increased the surface expression of TNF-R75. In addition, TNF-R75 transcripts were increased in resting and C. burnetii-stimulated monocytes from patients with ongoing endocarditis. On the other hand, TNF-R75 release was not related to TNF-alpha secretion. These results indicate that the modulation of TNF-R75 is a critical feature of the pathophysiology of Q fever endocarditis.


HLA-G as a new tumor biomarker: detection of soluble isoforms of HLA-G in the serum and saliva of patients with colorectal cancer.
Recent medical investigations suggest that HLA-G, due to its tolerogenic properties, can be used as a biomarker in the diagnosis, treatment, and prognosis of different neoplasms. This observational prospective pilot study aims at detecting sHLA-G in the serum and saliva of patients diagnosed with colorectal cancer (CRC). For this purpose, we compared the expression of sHLA-G from patients with a control sample from a healthy population. Using the specific enzyme-linked immunosorbent assay (ELISA) method, the expression of sHLA-G in the serum and saliva samples from patients affected by CRC (n = 20) and in a control sample (n = 10) were analyzed. The data showed that in patients with CRC, salivary sHLA-G values were significantly higher than in the control group (18.84 U/ml versus 6.3 U/ml, p = 0.036). In addition, higher levels of sHLA-G were observed in the saliva of patients with CRC in more advanced stages, compared with patients in early stages (24.2 U/ml vs. 8.1 U/ml, p = 0.019). A significant correlation was observed between the concentration of sHLA-G in the serum and saliva of the analyzed samples (Spearman correlation 0.7, p = 0.004). This study demonstrates, for the first time, the possibility of detecting sHLA-G in the saliva of patients with CRC, resulting in a less invasive alternative to venipuncture. Likewise, we propose that sHLA-G could be an attractive molecular target based on its significant high levels in advanced stages.


[Characteristics of the injuries to diaphyses of the long tubular bones in case of skew bending].
The present experimental study was designed to elucidate specific morphological features emerging from the destruction of diaphyses of long tubular bones undergoing a combined strain/stress impact. It is concluded that the species-specific signs of the injuries to the long tubular bones can be used for the purpose of their differential diagnosis from other types of injuries.


Oral Potentially Malignant Disorders.
Oral potentially malignant disorders (OPMDs) are precursor lesions that may undergo malignant transformation to oral cancer. These lesions most commonly present clinically as white patches (leukoplakia). However, they may also be red (erythroplakia), or red and white (erythroleukoplakia). There are many risk factors associated with the development of an OPMD, and with the risk of malignant transformation of the lesion. A biopsy with subsequent microscopic examination from the lesional tissue is necessary in identification of OPMD. This article reviews the clinical appearance of OPMDs, associated risk factors, diagnosis and histologic appearance, and treatment.


An alternative cost effectiveness analysis of ThinPrep in the Australian setting.
To assess the clinical and economic impacts of the use of liquid based cytology (LBC) in the Australian average risk population from the perspective of the public health care budget. Concerns over the evaluation of medical technologies in Australia, which are assessed by the Medicare Services Advisory Committee (MSAC), have been raised recently. We report on the evaluation of LBC, which although being widely adopted in other parts of the world, has, despite substantial uptake in the private sector in Australia, been rejected for public funding by MSAC. We used the health economic model developed by MSAC, but populated the model with the best available international data, sourced from a published review article. The economic model considered the clinical benefits and the costs arising from a biennial cervical screening programme. Net costs divided by life years saved is the cost per life year saved and this is reported as the incremental cost effectiveness. Populating the MSAC model with data on test performance showed that one type of LBC (ThinPrep) 'dominates' the conventional Pap smear in the screening of average risk women in the Australian setting. The health economic model created by MSAC predicts that ThinPrep dominates the conventional Pap as a screening test for cervical cancer. An additional 2240 high-grade lesions could be detected, resulting in 480 life years gained and delivering an expected saving to the health care system of $5,536,000 per annum if liquid based cytology replaced the conventional Pap.


Magnifying endoscopy with narrow-band imaging helps determine the management of gastric adenomas.
There are no clear clinical criteria for the management of gastric lesions diagnosed as adenomas (Vienna classification category 3) by pre-treatment biopsy. In the present study, we examined the feasibility of magnifying endoscopy with narrow-band imaging (ME-NBI) in discriminating early gastric cancers (Vienna classification category 4 or 5) from adenomas in lesions diagnosed as adenomas by pre-treatment biopsy. This was a single-center cross-sectional retrospective study at a tertiary referral center. One hundred thirty-seven consecutive cases of gastric lesions diagnosed as adenomas in pre-treatment forceps biopsy were examined with conventional non-magnifying endoscopy under white light, non-magnifying chromoendoscopy, and ME-NBI. We investigated the association between the final pathological diagnoses (carcinoma or adenoma) and the following factors: lesion size (mm), color (red or white), macroscopic type (depressed or others), presence of ulceration, and positive ME-NBI finding. The presence of an irregular microvascular pattern or an irregular microsurface pattern with a demarcation line between the lesion and the surrounding area was regarded as a positive ME-NBI finding. Lesion size was significantly larger in carcinomas than adenomas (P = 0.005). Depressed lesion (P = 0.011), red color (P < 0.001), and positive ME-NBI finding (P < 0.001) were significant predictive factors for carcinoma. Multivariate logistic regression confirmed that red color (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.26-7.34, P = 0.14) and a positive ME-NBI finding (OR 13.68, 95% CI 5.69-32.88, P < 0.001) were independent predictive factors for carcinomas. A positive ME-NBI finding was the strongest predictive factor. ME-NBI is useful in planning the management of lesions diagnosed as adenomas by pre-treatment forceps biopsy.


Effect of cell culture media on extracellular vesicle secretion from mesenchymal stromal cells and neurons.
Extracellular vesicles (EVs) secreted by neuronal cells in vitro have promising therapeutic potential for brain diseases. Optimization of cell culture conditions and methodologies for high-yield isolation of EVs for preclinical and clinical applications, however, remains a challenge. To probe the cell culture conditions required for optimal EV secretion by human-derived neuronal cells. First, we optimized the EV purification protocol using human mesenchymal stromal cell (MSC) cultures. Next, we compared the effects of different variables in human pluripotent stem cell (hPSC)-derived neuronal cultures on EV secretion. EVs were isolated from cell conditioned media (CCM) and control media with no cells (NCC) using ultrafiltration combined with size-exclusion chromatography (SEC). The hPSC neurons were cultured in 2 different media from which EVs were collected at 2 maturation time-points (days 46 and 60). Stimulation with 25 mM KCl was also evaluated as an activator of EV secretion by neurons. The collected SEC fractions were analyzed by nanoparticle tracking analysis (NTA), protein concentration assay, and blinded transmission electron microscopy (TEM). A peak in cup-shaped particles was observed in SEC fractions 7-10 of MSC samples, but not corresponding media controls, indicating successful isolation of EVs. Culture medium had no significant effect on EV yield. The EV yield of the samples did not differ significantly according to the culture media used or the cell maturation time-points. Stimulation of neurons with KCl for 3 h reduced rather than increased the EV yield. We demonstrated successful EV isolation from MSC and neuronal cells using an ultrafiltration-SEC method. The EV yield from MSC and neuronal cultures exhibited a large batch effect, apparently related to the culture media used, highlighting the importance of including NCC as a negative control in all cell culture experiments.


Effects of chlorpyrifos on cholinesterase activity and stress markers in the tropical reef fish Acanthochromis polyacanthus.
Tropical coastal ecosystems, including the Great Barrier Reef (GBR) of Australia are increasingly threatened by pollution; yet few studies have investigated the sensitivity of GBR species to these pollutants. Here we exposed juveniles of the tropical reef fish Acanthochromis polyacanthus (spiny damselfish) to three concentrations of the insecticide chlorpyrifos (CPF) and measured (i) muscle cholinesterase (ChE) activity; (ii) hepatic glutathione-S-transferase (GST) activity; and (iii) coenzyme Q (CoQ) redox balance, after 6h and 96h of exposure. After 96h, muscle ChE activity was significantly inhibited by 26%, 49% and 53% when fish were exposed to 1, 10 or 100μg/L CPF, respectively. Muscle ChE characterization revealed three types of ChEs, including two atypical forms. Hepatic CoQ antioxidant form significantly increased at 10μg/L after 6h of exposure, potentially demonstrating an early response to CPF-induced oxidative stress in liver. Hepatic GST was not affected by CPF exposure.


Porencephaly and schizencephaly in adopted infants. Frequency ascertainment in a risk group.
A formal inquiry on the health state of 1206 legally adopted children from Indonesia revealed cerebral palsy in 9 (0.9% of 1029 responses obtained), including two who had died. CT examination performed in 7 cases was abnormal in all. Four types of lesions were seen: 1. Bilateral full thickness porencephalies (BFTP lesion) in 4 cases, amounting to 0.4% of the total population on which response was obtained. 2. Full thickness porencephaly of the area of one internal carotid artery in 1 case. 3. Schizencephaly-like lesion in 1 case, confirmed by magnetic resonance imaging. 4. Supratentorial midline cyst resulting in hydrocephalus. The frequency of the BFTP lesion found in 4 out of 7 cerebral palsied investigated by CT is remarkable in view of its rarity in radiological studies on cerebral palsy and because of its relationship to prenatal rather than perinatal damage according to previous pathological studies. This is the first systematic study on the neurodevelopmental outcome of a group of adopted babies which indicates an increased risk to specific prenatal brain damage.


Alterations of beta-adrenoceptor-density and cAMP-synthesis in rat-erythrocytes after stress erythropoiesis.
During the maturation of red blood cells from rats after stress erythropoiesis, adenyl cyclase activity and beta-adrenoceptor density (pmoles/mg protein) decrease at distinctly different rates suggesting a different turnover of these membrane units.


Development of a homologous radioimmunoassay for red seabream follicle stimulating hormone and regulation of gonadotropins by GnRH in red seabream, Pagrus major.
Using a recombinant chimeric single-chain follicle stimulating hormone (FSH), we established a radioimmunoassay (RIA) for red seabream (Pagrus major) FSH (pmFSH) which became a powerful tool for studying reproductive physiology. We studied the profiles in plasma and pituitary concentrations of FSH and luteinizing hormone (LH) during sexual maturation. A pre-established RIA for red seabream LH was used for the LH measurements. The regulation of FSH and LH secretion from the pituitary was investigated using a gonadotropin-releasing hormone analog (GnRHa) in vivo and in vitro. Marked differences in plasma and pituitary FSH levels were observed between males and females; pituitary FSH content in males was much higher than that in females during all seasons, and plasma FSH levels in males were high during the spawning season, whereas those in females were unchanged. In contrast, plasma and pituitary levels of LH were elevated before and during the spawning season in males and females. Injecting or implanting (cholesterol pellet) a GnRHa into adult and juvenile red seabream resulted in significant increases in plasma LH concentrations; however, no significant change was observed in plasma FSH. Moreover, GnRHa stimulated only LH secretion in an in vitro experiment using dispersed pituitary cells. The discrete FSH and LH secretion profiles revealed suggest differential roles for the two gonadotropins during red seabream gametogenesis. In addition, the marked difference in pituitary FSH levels in males and females suggests the relative significance of FSH in male reproduction.


Mortality From Forces of Nature Among Older Adults by Race/Ethnicity and Gender.
Older adults are especially vulnerable to disasters due to high rates of chronic illness, disability, and social isolation. Limited research examines how gender, race/ethnicity, and forces of nature-defined here as different types of natural hazards, such as storms and earthquakes-intersect to shape older adults' disaster-related mortality risk. We compare mortality rates among older adults (60+ years) in the United States across gender, race/ethnicity, and hazard type using the Centers for Disease Control and Prevention's Wonder database. Our results demonstrate that older adult males have higher mortality rates than females. American Indian/Alaska Native (AI/AN) males have the highest mortality and are particularly impacted by excessive cold. Mortality is also high among Black males, especially due to cataclysmic storms. To address disparities, messaging and programs targeting the dangers of excessive cold should be emphasized for AI/AN older adult males, whereas efforts to reduce harm from cataclysmic storms should target Black older adult males.


Nivolumab versus pembrolizumab in previously-treated advanced non-small cell lung cancer patients: A propensity-matched real-world analysis.
Nivolumab and pembrolizumab have been the standard of care in patients with previously treated advanced non-small cell lung cancer (NSCLC). This study aimed to compare the efficacy and safety of nivolumab and pembrolizumab. We retrospectively reviewed data of advanced NSCLC patients with PD-L1 (Programmed death-ligand 1) [clone:22C3] positive tumors (Tumor proportion score [TPS] ≥ 1%) who had been treated with nivolumab or pembrolizumab as second- or subsequent line from 2015 to 2021.Propensity score matching was performed to reduce potential selection bias. We analyzed the clinical outcomes including objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs). Among a total of 202 eligible patients, 72 pairs of patients from each group were identified after propensity score matching. There were no significant differences in ORR, PFS, and OS between the two agents (nivolumab vs. pembrolizumab: ORR, 23.6% vs. 20.8%, median PFS, 3.7 months vs. 4.6 months, hazard ratio [HR] 1.02; 95% confidence interval [CI], 0.71 to 1.46; p = 0.92, and median OS, 27.4 months vs. 19.6 months, HR 0.78; 95% CI, 0.51 to 1.20; p = 0.24). Additionally, PFS was similar between the treatments in the PD-L1 TPS ≥ 50% subgroup (median PFS, 3.7 months vs. 4.6 months, HR 0.94; 95% CI, 0.56 to 1.59; p = 0.82) and PD-L1 TPS 1-49% subgroup (median PFS, 3.7 months vs.4.6 months, HR 1.13; 95% CI, 0.69 to 1.85; p = 0.61). There was also no significant difference in the frequency of grade ≥ 3 irAEs (9.7% vs. 11.1%; p = 1.0). There is no significant difference in the efficacy and safety between nivolumab and pembrolizumab in advanced NSCLC patients with PD-L1-positive tumors in the subsequent line setting.


Effects of long-term administration of alcoholic beverages on the kidney, heart, skeletal muscle and pancreas of rats. A histological study.
No pathological changes in the pancreas, kidneys or skeletal muscle were found in rats maintained for 8 to 9 months with a diet in which alcohol made up 50% of the total calories. An increase of the dietary fat content to 38% did not cause any fatty infiltration of the myocardium.


[Correction of a reperfusion dysfunction in acute intestinal obstruction].
An analysis of experimental investigations carried out in 32 dogs and 30 rabbits and laboratory data of 242 patients has shown that the application of antioxidant and antihypoxic medicines decrease reperfusion lesions and endotoxicosis in operative treatment of acute intestinal obstruction.


Molecular dynamics simulations of the interaction of wild type and mutant human CYP2J2 with polyunsaturated fatty acids.
The data presented here is part of a study that was aimed at characterizing the molecular mechanisms of polyunsaturated fatty acid metabolism by CYP2J2, the main cytochrome P450 enzyme active in the human cardiovasculature. This part comprises the molecular dynamics simulations of the binding of three eicosanoid substrates to wild type and mutant forms of the enzyme. These simulations were carried out with the aim of dissecting the importance of individual residues in the active site and the roles they might play in dictating the binding and catalytic specificity exhibited by CYP2J2. The data comprise: (a) a new homology model of CYP2J2, (b) a number of predicted low-energy complexes of CYP2J2 with arachidonic acid, docosahexaenoic acid and eicosapentaenoic acid, produced with molecular docking and (c) a series of molecular dynamics simulations of the wild type and four mutants interacting with arachidonic acid as well as simulations of the wild type interacting with the two other eicosanoid ligands. The simulations may be helpful in identifying the determinants of substrate specificity of this enzyme and in unraveling the role of individual mutations on its function. They may also help guide the generation of mutants with altered substrate preferences.


Applications of microfluidics for molecular diagnostics.
Diagnostic assays implemented in microfluidic devices have developed rapidly over the past decade and are expected to become commonplace in the next few years. Hundreds of microfluidics-based approaches towards clinical diagnostics and pathogen detection have been reported with a general theme of rapid and customizable assays that are potentially cost-effective. This chapter reviews microfluidics in molecular diagnostics based on application areas with a concise review of microfluidics in general. Basic principles of microfabrication are briefly reviewed and the transition to polymer fabricated devices is discussed. Most current microfluidic diagnostic devices are designed to target a single disease, such as a given cancer or a variety of pathogens, and there will likely be a large market for these focused devices; however, the future of molecular diagnostics lies in highly multiplexed microfluidic devices that can screen for potentially hundreds of diseases simultaneously.


Fractal analysis of rat brain activity after injury.
With application of the Higuchi algorithm, fractal dimension (FD) values of the electrocortical activity of the rat parietal cerebral and paravermal cerebellar cortex were calculated, before and after unilateral discrete injury of the left parietal cortex. Immediately following the first acute injury, in a group of six rats, a reversible increase in mean FD was found at the left (ipsilateral side to the injury) cerebral cortex, from 1.38 to 1.59, and at the left cerebellar cortex from 1.51 to 1.73. In addition, an indication of plastic changes after repeated (third) injury was found as an irreversible increase in mean FD: 1.54 on the left and 1.48 on the right side of parietal cortex.


The impact of organizational culture on the outcome of hospital care: after the implementation of person-centred care.
To measure the effect of organizational culture on health outcomes of patients 3 months after discharge. a quantitative study using Organizational Values Questionnaire (OVQ) and a health-related quality of life instrument (EQ-5D). A total of 117 nurses, 69% response rate, and 220 patients answered the OVQ and EQ-5D, respectively. The regression analysis showed that; 16% (R(2) = 0.02) of a decreased health status, 22% (R(2) = 0.05) of pain/discomfort and 13% (R(2) = 0.02) of mobility problems could be attributed to the combination of open system (OS) and Human Relations (HR) cultural dimensions, i.e., an organizational culture being dominated by flexibility. The results from the present study tentatively indicated an association between an organizational culture and patients' health related quality of life 3 months after discharge. Even if the current understanding of organizational culture, which is dominated by flexibility, is considered favourable when implementing a new health care model, our results showed that it could be hindering instead of helping the new health care model in achieving its objectives.


Fluorescence labels in kinases: a high-throughput kinase binding assay for the identification of DFG-out binding ligands.
Despite the hundreds of kinase inhibitors currently in discovery and pre-clinical phases, the number of kinase inhibitors which have been approved and are on the market remains low by comparison. This discrepancy reflects the challenges which accompany the development of kinase inhibitors which are relatively specific and less toxic. Targeting protein kinases with ATP-competitive inhibitors has been the classical approach to inhibiting kinase activity, but the highly conserved nature of the ATP-binding site contributes to poor inhibitor selectivity, issues which have particularly hampered the development of novel kinase inhibitors. We developed a high-throughput screening technology that can discriminate for inhibitors which stabilize the inactive "DFG-out" kinase conformation by binding within an allosteric pocket adjacent to the ATP-binding site. Here, we describe how to use this approach to measure the K (d) of ligands, as well as how to kinetically characterize the binding and dissociation of ligands to the kinase. We also describe how this technology can be used to rapidly screen small molecule libraries at high throughput.


Effect of anti-lipopolysaccharide of Escherichia coli antibody feeding for Holstein calves on ruminal lipopolysaccharide activity and plasma metabolites concentrations during pre- and post-weaning periods.
This study was performed to examine the effects of anti- lipopolysaccharide (LPS) of Escherichia coli chicken egg Yolk immunoglobulin (IgY) provided to calves for 7 weeks during the pre- and post-weaning periods on rumen LPS activity, plasma acute phase protein (APP) concentrations, and metabolic parameters. A total of 30 Holstein calves were randomly assigned to two groups of 15 each: an IgY group fed Anti-E. coli LPS IgY, and a control group fed whole egg powder as a placebo. The study was conducted on calves aged 3-10 weeks, weaned at 7 weeks. The ruminal LPS activity of the IgY group was approximately 60% lower than the control group at 10 weeks of age. Plasma APP and cytokine concentrations in the IgY group did not differ from those in the control group. The daily weight gain in the IgY group was significantly higher than the control group for the whole experimental period. Plasma albumin/globulin was lower (P<0.05), and plasma aspartate transferase concentration was higher (P<0.05) in the IgY group than in the control group during the experimental period. In conclusion, feeding Anti-E. coli LPS IgY for 7 weeks pre- and post-weaning remarkably reduced the rumen LPS activity and improved the daily weight gain. The impact of Anti-E. coli LPS IgY on LPS activities in the lower gastrointestinal tract, and elucidation as to the mechanism responsible for the improvement in daily weight gain require further investigation.


Gene conversion, unequal crossing-over and mispairing at a non-tandem duplication during meiosis of Saccharomyces cerevisiae.
We have developed a novel system to examine conversion, exchange and mispairing involving a non-tandem duplication of the ade8 locus in yeast by monitoring the segregation of heterozygous markers between the duplicated sequence. Plasmid Yrp17 carries the yeast selectable markers URA3+ and TRP1+. Yrp17 derivatives with a 4 kb insert carrying ade8-18 were used to clone the mutations trp1-1 and ura3-1 by gap repair. Integrants of the resulting plasmids at the Ade8 locus were crossed to yield diploid hybrids with a non-tandem duplication of Ade8 and heterozygosity for the plasmid markers between the duplicated sequences. 1192 complete, unselected asci were analyzed and 270 exhibiting recombination of the markers contributed by the plasmid were analyzed by Southern transfers to detect changes in plasmid sequences. Twenty-seven tetrads had unequal homologous exchanges and five had unequal sister-chromatid exchanges. Seven tetrads carry an additional copy of the integrated plasmid and ten are missing one. We propose that these two classes represent conversions of the entire 11 kb plasmid, which occur after misalignment and formation of an unpaired loop. Mispairing is a frequent event, and occurs in approximately fifty percent of all meioses. The system described provides a means to determine the meiotic rules of conversion, exchange and pairing for duplicated DNA sequences.


[Determination of a dimethylaniline mixture in the intermediate products for the production of semisynthetic penicillins].
A gas-chromatographic method for determination fo the content of dimethylaniline (DMA) in 6-aminopenicillanic acid, a semi-product for production of semi-synthetic antibiotics, was elaborated. The chloroform extracts of DMA from the alkaline solutions of the preparation were analysed in a gas chromatograph with a flame-ionization detector on a stainless steel column 2 m long and the inner diameter of 2 mm filled with 10 per cent OV-17 on chromosorb W-HMDS at a temperature of 112 degrees C. The minimum detectable amount of DMA was 5.10(-9) g. The assay error was +/- 5.35 per cent. The method may be used for the assay of other semi-synthetic antibiotics.


[Interconversion of stereochemically unstable chiral drugs. Part III: Using beta-cyclodextrin as a chiral stationary phase for HPLC separation of diazepam conformers coupled with an off-line NMR experiment].
Chiral beta-cyclodextrin was used to separate diazepam conformers. Several mobile phases of the composition acetonitrile/acetate buffer 200 mmol/l (pH=3.3, 5.5, 6.5) were employed for this purpose. As follows, the influence of addition of chiral beta-cyclodextrin to the mobile phase on diazepam separation was studied. The interconversion was a concurrence process of separation, resulting from stereolability of the diazepam molecule. The influences of temperature, flow rate, pH, and ionic strength of the mobile phase on interconversion and chromatographic parameters (retention factor and selectivity coefficient) were studied. Complementary off-line NMR measurements were carried out with the goal to confirm the structure of diazepam in the presence of an acid mobile phase.


Technique of simultaneous recording of EMG from various extraocular muscles under EOG control.
With this technique simultaneous recording of EMG is shown from various extra-ocular muscles. Electrodes are applied in the muscles during surgical procedures and recordings are performed without discomfort in the following days. The electrical signals are acquired at large bandwidth, and various off-line elaborations are possible. Preliminary results as well as technical details are presented.


The interactions of cetyltrimethylammonium with mitochondria: an uncoupler or a detergent?
The interactions of cetyltrimethylammonium (CTA) with mitochondria have been investigated. We confirm, as already observed in a previous paper, that this compound behaves as proton carrier (or uncoupler) of the oxidative phosphorylation, but evidences suggest that this compound enhances the membrane permeability to many other compounds such as sucrose. We conclude therefore that CTA as a detergent enhances membrane permeability to all ions including protons. Some evidences are also given that the inhibitory effect of CTA on the mitochondrial respiratory chain is a consequence of the swelling induced.


Tooth enamel protein, amelogenin, has a probable beta-spiral internal channel, Gln112-Leu138, within a single polypeptide chain: preliminary molecular mechanics and dynamics studies.
Molecular dynamics simulation, with backbone constraints for 20 ps of equilibration and simulation, of a repeating polypeptide segment, Gln-Pro-His-Gln-Pro-Leu-Gln-Pro-His-Gln-Pro-Leu-Gln-Pro-Met-(Gln-Pro-Leu )4, constituting residues 112-138 of bovine amelolgenin, a 19.35 kD hydrophobic protein, are discussed. It is generally believed that the above polypeptide segment is important for the interaction of amelogenin with Ca++ ions, which occurs in the early phases of enamel mineralization. An energetically stable structure of the above polypeptide with recurrent beta-turns is observed and contains a pore of approximately 1 A radius along the helical that can accommodate an unhydrated Ca++ ion. The length of the polypeptide possesses correct dimensions to span a bilayer. The proposed structure is unique among known polypeptide and protein structures.


The evidence of the release of prostaglandin-like material from rabbit kidney and guinea-pig lung by (minus)-trans-delta9-tetrahydrocannabinol.
Injection of (minus)-trans-delta9-tetrahydrocannabinol (THC) through the renal artery caused a decrease in perfusion pressure and an increase in urine produced by the isolated perfused rabbit kidney. Both effects of THC are inhibited by the prior addition of aspirin to the perfusion medium. THC also induced a dose-dependent increase in perfusion pressure on the isolated perfused lung of guinea-pig and the effluent from the lung produced a contraction on the isolated continuously superfused rat stomach fundus strip. These effects are prevented by the pretreatment of the lung with aspirin which inhibits the production of prostaglandins (PG) and SC 19220 which inhibits the pharmacological effects of PG.


Liquid chromatographic tandem mass spectrometric assay for simultaneous quantification of compound 97/78 and its in vivo metabolite 97/63, a novel trioxane antimalarial, in human plasma and its application to a protein binding study.
A sensitive, selective and specific LC-MS/ MS assay for simultaneous quantification of compound 97/78 and its active in vivo metabolite 97/63, a novel 1,2,4-trioxane antimalarial, in human plasma has been developed and validated using alpha-arteether as internal standard (IS). Extraction from plasma involves a simple protein precipitation method. The analytes were chromatographed on a Columbus C18 column with guard by isocratic elution with acetonitrile:ammonium acetate buffer (10 mM, pH 4.0) (80:20 v/v) as mobile phase at a flow rate of 0.45 mL min(-1) and analyzed in multiple reaction-monitoring (MRM) positive ion mode. The chromatographic run time was 4.0 min. The weighted (1/x2) calibration curves were linear over a range of 1.56-200 ng mL(-1) with correlation coefficients > 0.998. For both analytes, the limit of detection (LOD) and lower limit of quantification (LLOQ) were 0.5 ng mL(-1) and 1.56 ng mL(-1), respectively. The recovery of 97/78, 97/63 and IS from spiked control samples were > 90% and their matrix suppression obtained were < 8 %. The accuracy (% bias) and precision (%RSD) for both analytes were < 6.78%. Both analytes were stable after three freeze-thaw cycles (% deviation < 12.80), long-term for 30 days in plasma at -60 degrees C (% deviation < 14.38), for 8 h on bench top in plasma at ambient temperature (% deviation < 1.52) and also in the auto-sampler for 12 h (% deviation < 3.9%). The validated method was successfully applied to a protein binding study of compound 97/78 and metabolite 97/63 in human plasma. Furthermore, the validated method will be applicable to pharmacokinetics, bioavailability and metabolism in various clinical phases and in drug interaction studies.


96-hour methamphetamine self-administration in male and female rats: a novel model of human methamphetamine addiction.
Methamphetamine (MA) is a highly addictive psychostimulant drug of abuse for which no FDA-approved treatment exists. While high on MA, both male and female MA users report engaging in risky behaviors and are more likely to be involved in violent criminal activities and to engage in domestic and sexual violence. A unique aspect of MA is that it is typically used in binges. However, there is no animal model of MA self-administration that appears to represent a human MA self-administration binge. We recently developed a 96-hour MA self-administration paradigm in rats that more closely resembles how human MA users take the drug. Male and female rats were trained to self-administer MA for 96 consecutive hours for 5 weeks. Responding by female and male rats tended to escalate to binge-like behavior, as the animals responded continuously during their normal periods of activity as well as during their inactive periods for up to 72 h, followed by a crash of 6 or more hours. Thus, this 96-hour model of MA self-administration is a novel way to study MA addition in rats that may contribute to the development of improved treatments for recovering human MA users.


Programmable multivalent display of receptor ligands using peptide nucleic acid nanoscaffolds.
Multivalent effects dictate the binding affinity of multiple ligands on one molecular entity to receptors. Integrins are receptors that mediate cell attachment through multivalent binding to peptide sequences within the extracellular matrix, and overexpression promotes the metastasis of some cancers. Multivalent display of integrin antagonists enhances their efficacy, but current scaffolds have limited ranges and precision for the display of ligands. Here we present an approach to studying multivalent effects across wide ranges of ligand number, density, and three-dimensional arrangement. Using L-lysine γ-substituted peptide nucleic acids, the multivalent effects of an integrin antagonist were examined over a range of 1-45 ligands. The optimal construct improves the inhibitory activity of the antagonist by two orders of magnitude against the binding of melanoma cells to the extracellular matrix in both in vitro and in vivo models.


Microtubule affinity-regulating kinase 2 (MARK2) turns on phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) at Thr-313, a mutation site in Parkinson disease: effects on mitochondrial transport.
The kinase MARK2/Par-1 plays key roles in several cell processes, including neurodegeneration such as Alzheimer disease by phosphorylating tau and detaching it from microtubules. In search of interaction partners of MARK2, we identified phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), which is important for the survival of neurons and whose mutations are linked to familial Parkinson disease (PD). MARK2 phosphorylated and activated the cleaved form of PINK1 (ΔN-PINK1; amino acids 156-581). Thr-313 was the primary phosphorylation site, a residue mutated to a non-phosphorylatable form (T313M) in a frequent variant of PD. Mutation of Thr-313 to Met or Glu in PINK1 showed toxic effects with abnormal mitochondrial distribution in neurons. MARK2 and PINK1 were found to colocalize with mitochondria and regulate their transport. ΔN-PINK1 promoted anterograde transport and increased the fraction of stationary mitochondria, whereas full-length PINK1 promoted retrograde transport. In both cases, MARK2 enhanced the effects. The results identify MARK2 as an upstream regulator of PINK1 and ΔN-PINK1 and provide insights into the regulation of mitochondrial trafficking in neurons and neurodegeneration in PD.


Rabbit IgM: its isolation in high yield by a convenient procedure using serum from trypanosome-infected animals.
Rabbit sera contain little IgM. This is a major obstacle for its isolation. However, levels of IgM up to 10 mg/ml are found in rabbits infected with living trypanosomes. A simple procedure, involving gel filtration, standing in the cold, and agarose block electrophoresis is described which allows the isolation of IgM from these sera in 60% yield, with a purity of better than 90%.


Gastrointestinal hemorrhage due to Mallory-Weiss syndrome in an infant.
A Mallory-Weiss tear of the gastroesophageal mucosa is reported as an unusual cause of upper gastrointestinal bleeding in a 3-week-old infant. The lesion, documented by endoscopy, appeared to follow hiccups. The bleeding responded to conservative medical management and resolved without surgical intervention.


Kinetics of the uracil-DNA glycosylase/inhibitor protein association. Ung interaction with Ugi, nucleic acids, and uracil compounds.
The bacteriophage PBS2 uracil-DNA glycosylase inhibitor (Ugi) inactivates Escherichia coli uracil-DNA glycosylase (Ung) by forming an Ung.Ugi protein complex with 1:1 stoichiometry. Stability of the Ung.Ugi complex was demonstrated by the inability of free Ugi to exchange with Ugi bound in preformed complex. Ung was reacted with fluorescein 5-isothiocyanate to produce fluorescent-Ung (F-Ung), which retained full uracil-DNA glycosylase activity and susceptibility to Ugi inactivation. Addition of Ugi to F-Ung under steady-state conditions resulted in saturable (15%) fluorescence quenching at a F-Ung.Ugi ratio of 1:1.4. Dissociation constants determined for the F-Ung interaction with M13 DNA, uracil-containing DNA, and poly(U) equaled 600, 220, and 190 microM, respectively. While F-Ung associated with nucleic acid polymers was able to bind Ugi efficiently, F-Ung bound in the F-Ung.Ugi complex could no longer effectively bind nucleic acid. Stopped-flow kinetic analysis suggested the F-Ung/Ugi association was described by a two-step mechanism. The first step entailed a rapid pre-equilibrium distinguished by the dissociation constant Kd = 1.3 microM. The second step led irreversibly to the formation of the final complex and was characterized by the rate constant k = 195 s-1. We infer Ugi inactivates Ung through the formation of an exceptionally stable protein-protein complex.


Ethyl pyruvate attenuates isoproterenol-induced myocardial infarction in rats: Insight to TNF-α-mediated apoptotic and necroptotic signaling interplay.
The current study investigated the prophylactic effect of ethyl pyruvate (EP) in Isoproterenol (ISO) - induced myocardial infarction (MI). Ethyl pyruvate (EP) was given at a dose of 100 mg/kg i.p for 7 days, while isoproterenol (ISO) was administered at a dose of 10 mg/kg s.c. on the 6th and 7th days to induce MI. All parameters were assessed 24 and 48 h following treatment. Interestingly, EP pre-treatment significantly improved ISO-induced hemodynamic alterations and remarkably ameliorated serum levels of cardiac injury markers, Cardiac Troponin I (cTnI) and Cardiac Creatine Kinase (CK-MB). Also, EP notably suppressed levels of oxidative stress markers, total antioxidants (TAO) and malondialdehyde (MDA) as compared to ISO-treated group. Cardioprotective effects of EP were confirmed by histopathological examination. Moreover, EP remarkably attenuated ISO-induced elevation in Tumor Necrosis Factor Alpha (TNF-α) and Nuclear factor kappa-B p65 (NF-κB) expression, along with Interleukin-6 (IL-6), Monocyte chemoattractant protein 1 (MCP-1) and Inducible nitric oxide synthase (i-NOS) levels. Also, EP significantly diminished expression of apoptotic markers; caspase 8, cleaved caspase 3 and apoptotic regulator; cellular FLICE-like inhibitory protein (cFLIP). Finally, EP notably mitigated necroptotic mediators, phosphorylated receptor-interacting serine/threonine protein kinase 1 and 3 (p-RIPK1 and p-RIPK3), phosphorylated mixed lineage kinase domain-like protein (p-MLKL) and heat shock protein 70 (HSP 70) expression as compared to the ISO-treated group. Our study was the first to investigate the effect of EP on the necroptotic signaling. Taken together, EP conferred its cardioprotective effect against ISO-induced MI partially through mitigation of TNF-α and its downstream inflammatory, apoptotic and necroptotic signaling pathways.


New Chironomidae (Diptera) with elongate proboscises from the Late Jurassic of Mongolia.
Four new species of Chironomidae with well-developed elongate proboscises are described from a Late Jurassic site Shar Teg in SW Mongolia. These are named Cretaenne rasnicynisp. n., Podonomius blepharissp. n., Podonomius macromastixsp. n., ?Podonomius robustussp. n.


Electron probe X-ray microanalysis of human muscle biopsies.
The elemental composition of human muscle fibres have been determined by electron probe microanalysis. In order to distinguish between different types of fibres, two approaches were used. In one approach individual fibres were isolated, portions of them used for a typing by histochemical methods and the main part used for X-ray microanalysis. In the other approach the muscle biopsy was serial-sectioned, some sections used for a histochemical typing and the others (16 micrometer thick cryosections) used for X-ray microanalysis in th eelectron microscopy. The comparison of the ratios between P, S and K in Study No. 1 and 2 indicates different concentrations of sulphur in the subsarcolemmal zone and in the interior of the fibre. Both routes give information on all elements (except the ten lightest ones) contained in the fibres or in sections of them, provided the concentration is high enough. In order to obtain quantitative data, expressed as mmol/kgw, the spectra of the specimens were compared to those of standards of known composition and the data subjected to a so called ZAF-correction (corrections for the atomic number effect, absorption of X-rays in the specimen and secondary fluorescence). Quantitative data concerning phosphorus, sulphur, chlorine and potassium were obtained in Study No. 2. A significantly higher sulphur concentration was found in type IIA muscle fibres as compared to those of type I.


Myelin protein metabolism in demyelination and remyelination in the sciatic nerve.
Lysophosphatidylcholine (LPC) was injected intraneurally into the right sciatic nerve of a series of rats, leaving the left nerve as a control. At various time points up to 30 days after LPC treatment, the injected and control nerves were removed and incubated with [3H]amino acids, then purified myelin was prepared from the nerves. At all time points investigated the uptake of labeled amino acids was much higher in myelin proteins from the LPC-treated nerve than in those from the intact control nerve. [3H]Fucose uptake was also slightly increased. In the first week after LPC injection the increased amino acid incorporation was much greater in the myelin proteins of molecular weight higher than P0. From 10 days on, the smaller myelin proteins including P0, 19K, P1 and P2 showed the largest increase. From comparison of the morphology and biochemistry at 3 and 7 days after LPC injection, we propose that in the first 7 days, while myelin is degenerating, those proteins associated with Schwann cell or myelin reaction, interaction, and recognition functions are most stimulated metabolically, while after ten days the structural myelin proteins are actively resynthesized and the axon is remyelinated.


Spermatogenesis: borrowing the apoptotic machinery.
The apoptotic machinery is utilized for a wide variety of tasks during development. Recent work has uncovered a new, non-apoptotic role for these factors during the individualization process of maturing spermatids.


Sperm DNA fragmentation index does not correlate with the sperm or embryo aneuploidy rate in recurrent miscarriage or implantation failure patients.
The aneuploidy rate is higher in poor-quality sperm samples, which also have higher DNA fragmentation index values. The aim of this study was to assess the relationship between sperm DNA fragmentation in samples from infertile men belonging to couples with recurrent miscarriage or implantation failure and the aneuploidy rate in spermatozoa as well as in embryos from patients. This prospective study evaluated DNA damage and the aneuploidy rate in fresh and processed (density gradient centrifugation) ejaculated sperm as well as the aneuploidy rate in biopsied embryos from fertility cycles. Fluorescence in situ hybridization was used for the aneuploidy analysis. Results were compared using linear regression and analysis of variance. A total of 154 embryos were evaluated from 38 patients undergoing PGD cycles; 35.2% of the embryos were chromosomally normal. Analysis of the same sperm samples showed an increased DNA fragmentation after sperm preparation in 76% of the patients. There was no correlation between DNA fragmentation and the aneuploidy rate in embryos or in fresh or processed sperm samples. Sperm DNA fragmentation is not related to chromosomal anomalies in embryos from patients with recurrent miscarriage or implantation failure. However, we cannot rule out the possibility that a relationship between DNA fragmentation and aneuploidy exists for other causes of infertility. Furthermore, the different methods used to evaluate DNA fragmentation may produce different results.


Endogenous dopamine modifies electroresponsiveness of pars compacta cells in the guinea pig substantia nigra in vitro.
In the nigrostriatal pathway, dopamine is released not only from striatal nerve terminals, but also locally from the dendrites of nigrostriatal neurones within the substantia nigra itself. Exogenous dopamine is known to inhibit the firing of these neurones when applied directly to the substantia nigra in micromolar concentrations: but the amounts used are probably much higher than the endogenous concentration of the transmitter. Moreover, the direct, local blockade of nigral dopamine autoreceptors has not been reported to affect the firing rates of these neurones. The electrophysiological effects of endogenous dopamine were therefore examined using intracellular recordings from the substantia nigra in vitro. When slices of the midbrain were pharmacologically depleted of endogenous dopamine, selective membrane properties of nigrostriatal neurones were altered in a manner consistent with the effects of the exogenous transmitter. Similar changes were observed in control slices on exposure to the dopamine antagonist haloperidol. It is concluded that endogenous dopamine normally exerts a tonic influence on the electrical properties of nigrostriatal neurones.


Nonpapillary carcinoma in situ of the urinary bladder. A histopathologic study and mapping of the urothelial lesions.
Three cases of primary nonpapillary carcinoma of the urinary bladder diagnosed by urinary cytology and multiple biopsies were reported. Bladder specimens of two of the patients were totally embedded for step-sections that were mapped after histopathologic study. Atypical hyperplasia and carcinoma in situ with foci of microscopic invasion affected the bladder mucosa and extended continuously to the distal ureters as well as prostatic urethra. Multicentric distribuion of the abnormal epithelium was definite in one case, and the bladder mucosa was extensively denuded in the other case. Metastasis to one of the regional lymph nodes was noted in the remaining one case. The origin of Pagetoid cells occurring in two of the cases is obscure, but we presume that these cells may represent transformed tumor cells showing differentiation toward the surface umbrella cells, or they are derived from Brunn's nests where the cells may gain potential to differentiate to glandular epithelium.


Selenium status in neonates with connatal infection.
Infectious diseases impair Se metabolism, and low Se status is associated with mortality risk in adults with critical disease. The Se status of neonates is poorly characterised, and a potential impact of connatal infection is unknown. We hypothesised that an infection negatively affects the Se status of neonates. We conducted an observational case-control study at three intensive care units at the Charité-Universitätsmedizin Berlin, Germany. Plasma samples were collected from forty-four neonates. On the basis of clinical signs for bacterial infection and concentrations of IL-6 or C-reactive protein, neonates were classified into control (n 23) and infected (n 21) groups. Plasma Se and selenoprotein P (SePP) concentrations were determined by X-ray fluorescence and ELISA, respectively, at day of birth (day 1) and 48 h later (day 3). Se and SePP showed a positive correlation in both groups of neonates. Se concentrations indicative of Se deficit in adults (500 ng/l). During antibiotic therapy, SePP increased significantly from day 1 (1·03 (sd 0·10) mg/l) to day 3 (1·34 (sd 0·10) mg/l), indicative of improved hepatic Se metabolism. We conclude that both Se and SePP are suitable biomarkers for assessing Se status in neonates and for identifying subjects at risk of deficiency.


The curious case of processing unaccusative verbs in aphasia.
Individuals with agrammatic Broca's aphasia (IWBA) exhibit a delay in lexical activation in S-V-O word order sentences and delayed lexical reactivation in sentences that contain syntactic dependencies. This pattern is in contrast to neurologically unimpaired individuals who immediately evince lexical reactivation at the gap in sentences that contain syntactic dependencies. However, in the case of sentences that contain unaccusative verbs, neurologically unimpaired individuals also exhibit a delay in lexical reactivation. This delay provides a unique opportunity to further examine lexical delays in IWBA. The purpose of the current studies is to investigate the online comprehension of sentences that contain unaccusative verbs in IWBA and in a group of age-matched control (AMC) individuals. Cross-modal picture priming was used to test for priming of a displaced lexical item (direct object noun) immediately after the unaccusative verb (at the gap) during the ongoing auditory stream and at three additional time points downstream from the verb (500 ms, 750 ms, and 1,250 ms). Delayed reactivation of the displaced lexical item downstream from the gap (similar to prior reports of delayed reactivation with younger unimpaired listeners) for both the AMCs and the IWBA was found. These results provide support that IWBA do not evince a delayed time course of lexical reactivation for unaccusative verbs compared to neurologically unimpaired individuals.


Biomarkers for predicting the response of esophageal squamous cell carcinoma to neoadjuvant chemoradiation therapy.
This review summarizes and evaluates the literature regarding the biomarkers for predicting the response and/or prognosis of esophageal squamous cell carcinoma (ESCC) patients treated with neoadjuvant chemoradiation therapy (CRT). There are seven categories of molecules known to correlate with the response and/or prognosis: tumor suppressors (p53, p21), cell cycle regulators (Cyclin D1, CDC25B, 14-3-3sigma), DNA repair molecules (p53R2, ERCC1), drug resistance proteins [metallothionein (MT)], angiogenic factors (VEGF), molecules involved in cell proliferation/invasion/metastasis (Ki-67, COX-2) and hedgehog signaling molecules (Gli-1). Of the above molecules, the tumor suppressor p53 is expected to be a representative biomarker for predicting the response and prognosis. The cell cycle markers CDC25B and 14-3-3sigma have potential as response biomarkers independent of the p53 status. The DNA repair markers, p53R2 or ERCC1, angiogenic molecule (VEGF), and hedgehog signaling pathway factor Gli-1 also have potential to predict the response and prognosis of ESCC. However, there are still many unanswered questions with regard to predicting the clinical effects of neoadjuvant CRT.


[Thrombosis prevention with heparin/dihydroergotamine versus heparin/Sintrom in Ender nailing of pertrochanteric fractures].
The effect of either (randomized) Heparin/Dihydroergotamine (HDHE) or heparin-acenocoumarin (Hep/S) on the incidence of deep-vein thrombosis in the legs was studied in 212 women of more than 60 years of age with hip fractures. All patients were screened with the 125-I-fibrinogen uptake test (FUT) confirmed by a bilateral ascending venogram upon positive FUT. This revealed good sensitivity and specificity (85/84%) for the FUT. Deep vein thrombosis developed in 37.6% of the HDHE group and in 59.1% of the Hep/S group which was significantly different (p less than 0.005). The calculated thrombosis risk was significantly diminished (by 38% - p less than 0.005) in the HDHE group. Therefore we conclude that in traumatology Heparin/Dihydroergotamine seems to be the prophylaxis of choice.


On sitting and doing: ethnography as action in global health.
Contemporary discussions within the arenas of medical anthropology and global health are often restricted by the driving imperatives to "do something" about a particular health problem. Drawing on ethnographic fieldwork conducted in Nepal in 1997, which sought to follow the translation of AIDS prevention policies into local awareness, this paper addresses the need to revitalize theories of ethnography for an understanding of global health goals. The Nepal example underscores how the path toward decisions is never entirely clear, nor is it always obvious who benefits or loses from different approaches, even as public health discourse seeks to set a strict agenda around what the problem is and what should be done about it. Ethnography shows that definitions of what matters as well as understandings of why certain things matter are formulated from specific social locations. The paper therefore advocates for a practice of patient ethnographic "sitting" as a means to understanding, as a form of critical reflexivity, and as a diagnostic of the politics of relevance.


ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model.
Angiogenesis inhibitors have been used to treat some cancers, but the therapeutic potential of these agents for gastric cancer has remained unclear. To investigate their therapeutic potential, we examined the effect of ZD6474, an agent that selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2; KDR) tyrosine kinase and epidermal growth factor receptor (EGFR) tyrosine kinase, in a highly metastatic orthotopic model using an undifferentiated gastric cancer cell line, 58As1. ZD6474 (100 mg/kg/day, p.o., 2 weeks) significantly inhibited tumor growth (p < 0.05 vs. control) and reduced tumor dissemination into the peritoneal cavity (p < 0.05 vs. control). In addition, to identify putative tumor biomarkers that would reflect the effects of ZD6474 treatment in clinical settings, we examined the gene expression profiles of implanted gastric tumors treated with ZD6474 in vivo. Twenty-eight candidate genes were identified, including IGFBP-3, ADM, ANGPTL4, PLOD2, DSIPI, NDRG1, ENO2, HIG2 and BNIP3L, which are known to be hypoxia-inducible genes. These genes and gene products may be useful biomarkers for monitoring the effects of ZD6474 treatment. ZD6474 also improved the survival of mice with implanted another undifferentiated gastric cancer cell line, 44As3. In conclusion, our results suggest that ZD6474 may have clinical activity against gastric cancer, particularly undifferentiated gastric cancer with peritoneal dissemination. We also identified putative biomarkers for monitoring the pharmacodynamic effects of ZD6474 by gene expression profiling.


Venous lakes: treatment by infrared coagulation.
A new treatment for venous lakes (Bean and Walsh, 1956) has been devised using an infrared coagulator. The solid light guide with its sapphire cap enables the ectatic vessels to be compressed prior to coagulation, minimising the energy required to destroy the vessels. We have successfully treated 10 lesions with a pulse duration of 1.125 seconds.


Long-term incidence and predictive factors of thromboembolic events after a cryoballoon ablation for atrial fibrillation.
Long-term outcomes in terms of thromboembolic events (TEs) are poorly described after cryoballoon pulmonary vein isolation (cryo-PVI) for atrial fibrillation (AF). We evaluated the long-term incidence and predictive factors of TE after cryo-PVI. All consecutive patients who underwent cryo-PVI for paroxysmal or persistent AF between November 2012 and October 2017 were included. They were prospectively followed for at least 12 months in the ablation center and then by their cardiologist. Data on all ischemic events (stroke, transient ischemic attack (TIA), systemic embolism) were collected. In total, 450 patients (78% men, median age 61 years) were included. The mean CHA2DS2-VASc score was 1.6 ± 1.3 and 26 patients (6%) had a history of stroke/TIA before the procedure. OAT was discontinued for 75 patients (17%) after the procedure, among whom 50 (67%) had no indication for long-term anticoagulation. Six patients experienced an ischemic event, all considered as a TE: three strokes, two TIAs, and one acute lower-limb ischemia. The mean follow up was 30 months. Thus, the incidence of TE was 0.53%/year. Three of the six patients who experienced a TE had no recurrence of atrial arrhythmia documented before, at the time, or after the event. All patients who experienced a TE had a class I or class IIa indication for long-term anticoagulation. After multivariate analysis, the CHA2DS2-VASc Score (p = .0005) was a predictor of TEs. The long-term incidence of TEs after cryo-PVI was 0.53%/year. The CHA2DS2-VASc Score was the only independent predictor of TEs.


Atomoxetine/Methylphenidate Effects on Social Play Behavior.
Researchers at Utrecht University, The Netherlands, and University "Roma Tre," Rome, Italy, studied the neural substrates of the previously identified social play-suppressant effects of methylphenidate (MPH) and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD).


Generation, evolution, interfering factors, applications, and challenges of patient-derived xenograft models in immunodeficient mice.
Establishing appropriate preclinical models is essential for cancer research. Evidence suggests that cancer is a highly heterogeneous disease. This follows the growing use of cancer models in cancer research to avoid these differences between xenograft tumor models and patient tumors. In recent years, a patient-derived xenograft (PDX) tumor model has been actively generated and applied, which preserves both cell-cell interactions and the microenvironment of tumors by directly transplanting cancer tissue from tumors into immunodeficient mice. In addition to this, the advent of alternative hosts, such as zebrafish hosts, or in vitro models (organoids and microfluidics), has also facilitated the advancement of cancer research. However, they still have a long way to go before they become reliable models. The development of immunodeficient mice has enabled PDX to become more mature and radiate new vitality. As one of the most reliable and standard preclinical models, the PDX model in immunodeficient mice (PDX-IM) exerts important effects in drug screening, biomarker development, personalized medicine, co-clinical trials, and immunotherapy. Here, we focus on the development procedures and application of PDX-IM in detail, summarize the implications that the evolution of immunodeficient mice has brought to PDX-IM, and cover the key issues in developing PDX-IM in preclinical studies.


Influence of Pre-treatment Saliva Microbial Diversity and Composition on Nasopharyngeal Carcinoma Prognosis.
The human microbiome has been reported to mediate the response to anticancer therapies. However, research about the influence of the oral microbiome on nasopharyngeal carcinoma (NPC) survival is lacking. We aimed to explore the effect of oral microbiota on NPC prognosis. Four hundred eighty-two population-based NPC cases in southern China between 2010 and 2013 were followed for survival, and their saliva samples were profiled using 16s rRNA sequencing. We analyzed associations of the oral microbiome diversity with mortality from all causes and NPC. Within- and between-community diversities of saliva were associated with mortality with an average of 5.29 years follow-up. Lower Faith's phylogenetic diversity was related to higher all-cause mortality [adjusted hazard ratio (aHR), 1.52 (95% confidence interval (CI), 1.06-2.17)] and NPC-specific mortality [aHR, 1.57 (95% CI, 1.07-2.29)], compared with medium diversity, but higher phylogenetic diversity was not protective. The third principal coordinate (PC3) identified from principal coordinates analysis (PCoA) on Bray-Curtis distance was marginally associated with reduced all-cause mortality [aHR, 0.85 (95% CI, 0.73-1.00)], as was the first principal coordinate (PC1) from PCoA on weighted UniFrac [aHR, 0.86 (95% CI, 0.74-1.00)], but neither was associated with NPC-specific mortality. PC3 from robust principal components analysis was associated with lower all-cause and NPC-specific mortalities, with HRs of 0.72 (95% CI, 0.61-0.85) and 0.71 (95% CI, 0.60-0.85), respectively. Oral microbiome may be an explanatory factor for NPC prognosis. Lower within-community diversity was associated with higher mortality, and certain measures of between-community diversity were related to mortality. Specifically, candidate bacteria were not related to mortality, suggesting that observed associations may be due to global patterns rather than particular pathogens.


A further insight into methyltestosterone metabolism: New evidences from in vitro and in vivo experiments.
Although the metabolism of methyltestosterone (MT) has been extensively studied since the 1950s using different techniques, the aim of this study was to investigate the hydroxylation in positions C2, C4 and C6 after in vitro experiments and in vivo excretion studies using gas chromatography time-of-flight (GC/TOF) and gas chromatography/tandem mass spectrometry (GC/MS/MS). The results could be influenced by the mass spectrometric analyser used. Incubations were carried out with human liver microsomes and six enzymes belonging to the cytochrome P450 family using MT as a substrate. The trimethylsilyl derivatives of the samples were analysed using GC/TOF and GC/MS/MS once the correct MS/MS transitions had been selected, mainly for 6-hydroxymethyltestosterone (6-OH-MT) to avoid artefact interferences. A urinary excretion study was then performed after the administration of a 10 mg single oral dose of MT to a volunteer. The formation of hydroxylated metabolites of MT in the C6, C4 and C2 positions after both in vitro and in vivo experiments was observed. Sample evaluation using GC/TOF showed an interference for 6-OH-MT that could only be resolved in GC/MS/MS by monitoring specific transitions. The transitory detection of these hydroxylated metabolites in urine agrees with previous investigations that had described this metabolic route as being of little significance. In doping analysis, the formation of 4-hydroxymethyltestosterone (oxymesterone) from MT cannot be underestimated. Although it is only detected as a minor and short-term excretion metabolite, it cannot be overlooked as it was found in both in vitro and in vivo experiments. The use of a combination of different mass spectrometric instruments allowed reliable conclusions to be reached, and it was shown that special attention must be given to artefact formation.


Comparative calorimetric studies on the dynamic conformation of plant 5S rRNA. I. Thermal unfolding pattern of lupin seeds and wheat germ 5S rRNAs, also in the presence of magnesium and sperminium cations.
An attempt has been made to correlate differential scanning calorimetry melting profiles of 5S rRNAs from lupin seeds (L.s.) and wheat germ (W.g.) with their structure. It is suggested that the observed differences in thermal unfolding are due to differences in RNA nucleotide sequence and as a consequence in higher order structures. Interesting effects induced by magnesium cation, perprotonated and permethylated sperminium tetracations are discussed. It is suggested that the difference in the stabilizing effect of the three cations results from different mode of their interactions with RNA. "Pure" electrostatic interactions expected for permethylated tetracations are rather weak due to the steric hindrance around each positively charged nitrogen atom. Electrostatic interactions of the other two cations are significantly enhanced by coordination bonding for magnesium and by hydrogen bonding for protonated sperminium cation.