The length of susceptibility vessel sign predicts early neurological deterioration in minor acute ischemic stroke with large vessel occlusion.
Patients with acute large vessel occlusion (LVO) presenting with minor stroke are at risk of early neurological deterioration (END). The present study aimed to evaluate the frequency and potential predictors of END in patients with medical management and LVO presenting with minor stroke. The relationship between SVS length and END was also investigated. This was a prospective multicenter study. Consecutive patients were collected with anterior circulation. LVO presented with minor stroke [National Institutes of Health Stroke Scale (NIHSS) ≤ 4] within 24 h following onset. END was defined as a deterioration of NIHSS ≥4 within 24 h, without parenchymal hemorrhage. The length of the susceptibility vessel sign (SVS) was measured using the T2* gradient echo imaging. A total of 134 consecutive patients with anterior circulation LVO presenting with minor stroke were included. A total of 27 (20.15%) patients experienced END following admission. Patients with END exhibited longer SVS and higher baseline glucose levels compared with subjects lacking END (P < 0.05). ROC curve analysis indicated that the optimal cutoff point SVS length for END was SVS ≥ 9.45 mm. Multivariable analysis indicated that longer SVS [adjusted odds ratio (aOR), 2.03; 95% confidence interval (CI), 1.45-2.84; P < 0.001] and higher baseline glucose (aOR,1.02; 95% CI, 1.01-1.03; P = 0.009) levels were associated with increased risk of END. When SVS ≥ 9.45 mm was used in the multivariate logistic regression, SVS ≥ 9.45 mm (aOR, 5.41; 95%CI, 1.00-29.27; P = 0.001) and higher baseline glucose [aOR1.01; 95%CI, 1.00-1.03; P = 0.021] were associated with increased risk of END. END was frequent in the minor stroke patients with large vessel occlusion, whereas longer SVS and higher baseline glucose were associated with increased risk of END. SVS ≥ 9.45 mm was a powerful independent predictor of END.


Is cardiac test availability a significant factor in weekend delays in discharge for chest pain patients?
The authors assessed whether the lack of weekend cardiac test availability significantly contributed to weekend delays in hospital discharge for "low-risk" chest pain patients. Mean lengths of stay were compared for late-week versus early-week admissions. Patients with late-week admissions had a 19% greater length of stay than did patients admitted earlier in the week (2.36 +/- 1.87 vs 1.91 +/- 1.21 days, p = 0.10, with p = 0.015 after adjusting for severity of illness). Cardiac diagnostic tests were ordered for only 4% of study patients. Therefore, the "weekend effect" existed in an environment where cardiac diagnostic tests were infrequently ordered.


In situ crosslinked biodegradable hydrogels loaded with IL-2 are effective tools for local IL-2 therapy.
We investigated the therapeutic efficacy of recombinant human interleukin-2 (rhIL-2)-loaded, in situ gelling, physically crosslinked dextran hydrogels, locally applied to SL2 lymphoma in mice. The physical crosslinking was established by stereocomplex formation between d-lactic acid oligomers and l-lactic acid oligomers grafted separately to dextrans. The stereocomplex hydrogel as described in our manuscript has several favourable characteristics, which enables its use as system for the controlled release of pharmaceutically active proteins. Firstly, the hydrogel system is a physically crosslinked system. In physically crosslinked gels, the use of chemical crosslinking agents is avoided. Such agents can potentially inactivate the protein and can covalently link the protein to the hydrogel network. Secondly, the hydrogel formation takes place at room temperature and physiological pH, and, importantly, in an all-aqueous environment. All factors are important to preserve the three-dimensional structure, and thus the biological activity, of the protein to be entrapped and released from the gels. Thirdly, the gel formation does not occur instantaneously. This means that a liquid formulation can be injected which solidifies after injection (in situ gel formation is possible). Fourthly, no pH drop during degradation is expected during degradation. As a control, free rhIL-2 was administered locally in either a single injection or at five consecutive days. All mice received the same total dose of rhIL-2. The rhIL-2-loaded hydrogels released most IL-2 over a period of about 5 days. The biocompatibility and biodegradability of the gels were excellent, as there were no acute or chronic inflammatory reaction and as the gels were replaced completely by fibroblasts after 15 days. The therapeutic efficacy of rhIL-2-loaded in situ gelled hydrogels is very good, as was demonstrated in DBA/2 mice bearing SL2. The therapeutic effect of a single application of gels loaded with 1 x 10(6) IU rhIL-2 is at least comparable to the therapeutic effect of injection of an equal dose of free rhIL-2. All mice cured with rhIL-2-loaded hydrogels survived a subsequent challenge, rejecting 10(6) intraperitoneal (i.p.) injected SL2 cells. In conclusion, this study demonstrates that in situ gelling, physically crosslinked dextran hydrogels slowly release encapsulated rhIL-2 in such a way that it is intact and biologically and therapeutically active. These hydrogels may greatly enhance the clinical applicability of rhIL-2 immunotherapy as only a single treatment is required and as these hydrogels are completely biodegradable.


Intramolecular hydrogen bonding: a potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase.
Selective neuronal nitric oxide synthase (nNOS) inhibitors have therapeutic applications in the treatment of numerous neurodegenerative diseases. Here we report the synthesis and evaluation of a series of inhibitors designed to have increased cell membrane permeability via intramolecular hydrogen bonding. Their potencies were examined in both purified enzyme and cell-based assays; a comparison of these results demonstrates that two of the new inhibitors display significantly increased membrane permeability over previous analogs. NMR spectroscopy provides evidence of intramolecular hydrogen bonding under physiological conditions in two of the inhibitors. Crystal structures of the inhibitors in the nNOS active site confirm the predicted non-intramolecular hydrogen bonded binding mode. Intramolecular hydrogen bonding may be an effective approach for increasing cell membrane permeability without affecting target protein binding.


Structure-activity relationships (SAR) of some tetracyclic heterocycles related to the immunosuppressive agent Brequinar Sodium.
The structure-activity relationships of some tetracyclic heterocycles related to Brequinar were explored. Activities as inhibitors of dihydroorotate dehydrogenase and the mixed lymphocyte reaction are related to ring system, heteroatom placement, and pendant ring substitution.


Assignment of a gene for uridine diphosphate galactose-4-epimerase to human chromosome 1 by somatic cell hybridization, with evidence for a regional assignment to 1pter yields 1p21.
The presence of human uridine diphosphate galactose-4-epimerase (GALE) was found to correlate with the presence of chromosome 1 in somatic cell hybrids between man and mouse. The gene for GALE can therefore be assigned to human chromosome 1. Using a chromosome 1 rearrangement, we have been able to regionally assign GALE to the pter yields p21 region.


Liquid chromatography-mass spectrometry/mass spectrometry method development for drug metabolism studies: Examining lipid matrix ionization effects in plasma.
Glycerophosphocholines (GPCho's) are known to cause liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) matrix ionization effects during the analysis of biological samples (i.e. blood, plasma). We have developed a convenient new method, which we refer to as "in-source multiple reaction monitoring" (IS-MRM), for detecting GPCho's during LC-MS/MS method development. The approach uses high energy in-source collisionally induced dissociation (CID) to yield trimethylammonium-ethyl phosphate ions (m/z 184), which are formed from mono- and disubstituted GPCho's. The resulting ion is selected by the first quadrupole (Q1), passed through the collision cell (Q2) in the presence of collision gas at low energy to minimize fragmentation, and m/z 184 selected by the third quadrupole. This approach can be combined with standard multiple reaction monitoring (MRM) transitions with little compromise in sensitivity during method development and sample analysis. Hence, this approach was used to probe ionization matrix effects in plasma samples. The resulting information was employed to develop LC-MS/MS analyses for drugs and their metabolites with cycle times less than 5 min.


Prevalence and risk factors of erosive tooth wear among young adults in the Singapore military.
Erosive tooth wear (ETW) is defined as the irreversible chemo-mechanical loss of dental hard tissues without plaque or bacteria and has been a growing phenomenon in the general population worldwide. The aim of this study was to determine the prevalence of ETW and the associated risk factors among young military personnel in Singapore. This cross-sectional study consisted of a questionnaire and clinical examination of military personnel between 18 and 25 years. The questionnaire collected information on demographics, medical and dental history, lifestyle and dietary habits. Tooth wear was clinically evaluated using the Basic Erosive Wear Examination (BEWE) index. The participants were profiled into four risk categories (none, low, moderate, severe) based on the sum score. Multivariable logistic regression analysis was performed to determine the risk factors associated with the presence of ETW. Out of 1296 participants evaluated, 21.8% of them had ETW. The anterior sextants were more affected by erosion than posterior sextants for both arches. The risk factors significantly associated with ETW were GERD (OR = 2.83, p = 0.041), presence of self-reported TMD symptoms (OR = 2.51, p < 0.001), acidic food (OR = 2.03, p < 0.001) and drinks (OR = 3.07, p < 0.001), high caries risk (OR = 4.59, p < 0.001) and toothbrush stiffness (OR = 4.67, p < 0.001). ETW is prevalent among the young military population, with over half of the population at a risk of ETW. Gastric reflux disease, TMD, acidic diet, dental caries susceptibility and the use of stiff toothbrushes were identified as significant risk factors. A large proportion of young military personnel exhibited mild to moderate risk of ETW. Dental professionals can identify risk-susceptible individuals at a young age and educated them with preventive measures and dietary interventions to prevent the progression of the condition.


Neoglycoprotein and Glycoprotein Printing on a Hydrogel Functionalized Microarray Surface and Incubation with Labeled Lectins.
Glycan microarrays are widely used to elucidate carbohydrate binding specificity and affinity of various analytes including proteins, microorganisms, cells, and tissues. Glycan microarrays comprise a wide variety of platforms, differing in surface chemistry, presentation of carbohydrates, carbohydrate valency, and detection strategies, all of which impact on analyte performance. This chapter describes detailed methods for printing neoglycoprotein and glycoprotein microarrays on hydrogel-coated slides and incubation of these glycan microarrays with fluorescently labeled lectins.


Is a Wider Margin (2 cm vs. 1 cm) for a 1.01-2.0 mm Melanoma Necessary?
The current NCCN recommendation for resection margins in patients with melanomas between 1.01 and 2 mm deep is a 1-2 cm radial margin. We sought to determine whether margin width had an impact on local recurrence (LR), disease-specific survival (DSS), and type of wound closure. Melanomas measuring 1.01-2.0 mm were evaluated at a single institution between 2008 and 2013. All patients had a 1 or 2 cm margin. We identified 965 patients who had a 1 cm (n = 302, 31.3 %) or 2 cm margin (n = 663, 68.7 %). Median age was 64 years, and 592 (61.3 %) were male; 32.5 and 48.7 % of head and neck and extremity patients had a 1 cm margin versus 18.9 % of trunk patients (p < 0.001). LR was 2.0 and 2.1 % for a 1 and 2 cm margin, respectively (p = not significant). Five-year DSS was 87 % for a 1 cm margin and 85 % for a 2 cm margin (p = not significant). Breslow thickness, melanoma on the head and neck, lymphovascular invasion, and sentinel lymph node biopsy (SLNB) status significantly predicted LR on univariate analysis; however, only location and SLNB status were associated with LR on multivariate analysis. Margin width was not significant for LR or DSS. Wider margins were associated with more frequent graft or flap use only on the head and neck (p = 0.025). Our data show that selectively using a narrower margin of 1 cm did not increase the risk of LR or decrease DSS. Avoiding a 2 cm margin may decrease the need for graft/flap use on the head and neck.


Analysis of antigen expression on human spermatozoa by means of monoclonal antibodies.
Hybridoma cell lines were obtained by fusing NS-1 mouse myeloma cells with splenocytes from female mice immunized with whole washed human spermatozoa. Nine clonally derived cell lines were selected which secrete monoclonal antibodies against integral spermatozoan antigens. Immunofluorescence studies showed specific binding of the individual monoclonal antibodies to localized regions of the sperm cell: acrosomal cap, equatorial segment, and midpiece. Five of these antibodies also recognized antigenic determinants of isolated acrosin. The monoclonal antibodies provide probes for the immunochemical characterization of sperm antigens and for the elucidation of the role of these antigens in spermatozoan function.


Synthesis and evaluation of aminopyridine derivatives as potential BACE1 inhibitors.
To identify a new non-peptidyl BACE1 inhibitor, we focused on the aminopyridine structure, which binds to the active sites of BACE1. Synthesis of aminopyridine derivatives and evaluation of inhibitory activity against rBACE1 are described. The 2-aminopyridine moiety and/or 3-methoxybenzaldehyde could be converted to terminal acetylene derivatives by the Sonogashira method. Sonogashira or Glaser cross-coupling reactions with the corresponding derivatives followed by hydrogenation could derive the designed compounds. Although inhibitory activities of the synthetic compounds against rBACE1 were weak, the aminopyridine motif has potential as a BACE1 inhibitor.


Thioredoxin-mediated redox control of human T cell lymphotropic virus type I (HTLV-I) gene expression.
Thioredoxin (TRX) is a small ubiquitous protein with multiple biological functions, including the thiol-mediated redox-regulation of gene expression. We have previously demonstrated that human TRX is overexpressed as a major protein oxidoreductase in human T cell lymphotropic virus type I (HTLV-I)-infected cells. In the present study, we investigated the relationship between TRX and viral gene expression in HTLV-I infection. To study the mechanism that causes overexpression of TRX in HTLV-I-infected cells, we first examined the effect of the HTLV-I transactivator, Tax, on TRX expression. Induction of HTLV-I Tax protein increased the expression of TRX protein in a Tax-transfected Jurkat cell line, JPX-9. Moreover, chloramphenicol acetyltransferase (CAT) analysis with a reporter gene containing the TRX promoter revealed that Tax activates the transcription of TRX gene. To study the role of overexpressed TRX in HTLV-I infection, we next examined the effect of TRX on HTLV-I long terminal repeat (LTR)-mediated transcription using CAT analysis. In an HTLV-I-infected human T cell line MT-2, the HTLV-I LTR transactivation was suppressed by the overexpression of wild-type TRX, but activated by the introduction of inactive mutant TRX. Moreover, in HTLV-I negative Jurkat T cells, the HTLV-I LTR transactivation induced by Tax was also repressed by overexpression of wild-type TRX. Because cellular redox changes were shown to affect the HTLV-I gene expression, it is likely that TRX modulates the HTLV-I gene expression by regulating cellular redox state. Taken together, these findings suggest that overexpressed TRX, which is induced by HTLV-I Tax, may play an important role in HTLV-I infection through the negative regulation of viral gene expression.


Neuro-imaging of cerebral ischemic stroke.
Major progress has recently been made in the neuro-imaging of stroke as a result of improvements in imaging hardware and software. Imaging may be based on either magnetic resonance imaging (MRI) or computed tomography (CT) techniques. Imaging should provide information on the entire vascular cervical and intracranial network, from the aortic arch to the circle of Willis. Equally, it should also give information on the viability of brain tissue and brain hemodynamics. CT has the advantage in the detection of acute hemorrhage whereas MRI offers more accurate pathophysiological information in the follow-up of patients.


Intramedullary cavernous angiomas of the spinal cord: report of six cases.
The authors report six cases of intramedullary cavernoma. Symptoms evolved by episodes of stepwise neurologic deterioration or slow progression. All patients had preoperative and postoperative magnetic resonance imaging (MRI). Removal of the cavernoma was total in all cases and in one a transthoracic approach was performed because of the ventral and superficial position of the lesion. At follow-up, ranging from 6 to 18 months, two patients improved, two were unchanged, and one had deteriorated. Prognosis was influenced by the length of clinical history and the severity of preoperative symptoms. The principal clinical and therapeutic aspects of cavernoma are discussed in light of the published data.


CT bronchus sign in malignant solitary pulmonary lesions: value in the prediction of cell type.
The aim of this study was to evaluate differences in the prevalence of patterns of CT bronchus sign in malignant solitary pulmonary lesions (SPLs), according to their histologic cell types and with respect to size, location, and degree of cell differentiation. Computed tomography scans of 78 patients, in whom pathologically confirmed malignant SPLs with CT bronchus sign were present, were randomly selected and reviewed by two radiologists under consensus. All 78 were CT scans done using spiral technique with 10-mm collimation and 10-mm reconstruction intervals with enhancement, and 75 included additional high-resolution CT scans. Lesions were classified into four cell types as squamous cell carcinoma (n = 24), small cell carcinoma (n = 12), adenocarcinoma (n = 23), bronchioloalveolar carcinoma (BAC; n = 9), and others (n = 12), into three degrees of differentiation, into three size groups, and according to location (central or peripheral). Patterns of CT bronchus sign were classified into abruptly obstructing (I), patent (II), displacing (III), or tapered narrowing (IV) types. The relationships between the patterns of CT bronchus sign and cell type and degree of cell differentiation were evaluated. Eighty patterns of CT bronchus sign were observed in 78 patients. According to cell type, squamous cell carcinoma showed most often type-I pattern (45.8%) but no type-II pattern, which was the most common pattern observed in BAC (77.8%) and adenocarcinoma (34.8%; p<0.01). Small cell carcinoma showed a varied distribution among the four patterns of CT bronchus sign. According to location, in central squamous cell carcinomas, type-I pattern was more common(55%; p<0.01). Bronchioloalveolar carcinoma showed more peripheral lesions and in both central and peripheral lesions, type-II pattern was significantly more common (100 and 66.7%; p<0.01). In SPLs with CT bronchus sign of obstructing pattern, especially if central location, squamous cell carcinoma should be suspected, whereas in SPLs with patent CT bronchus sign, regardless of the location, the strong possibility of BAC should be considered.


The cochlear implant.
The cochlear implant offers an alternative to selected profoundly deaf patients in whom conventional treatments or prostheses have been unsuccessful. Substantial benefits have been obtained by patients, with apparently minimal risk. There have been no serious surgical complications and only a few postoperative problems, which were remedied satisfactorily. The device has continued to function in patients over a period of years, and in cases of internal coil failure it has been removed and replaced. Replacement devices seem to function as well as the patient's first device. There has been no evidence of any decrement in performance after years of electrical stimulation or any measurable adverse effects. The cochlear implant is now widely available and should be considered an option to be offered to appropriate patients.


Potent desensitization of human P2X3 receptors by diadenosine polyphosphates.
In this study, the receptor desensitizing effects of diadenosine polyphosphates at recombinant human P2X3 (hP2X3) receptors were examined. Administration of Ap3A, Ap4A, Ap5A or Ap6A inhibited the hP2X3 receptor-mediated response to a subsequent application of 3 muM alphabeta-methyleneATP (alphabeta-meATP), in a concentration-dependent manner, with IC50 values 2707, 42, 59 and 46 nM, respectively. These agonists did not desensitize alphabeta-meATP responses mediated by the slowly desensitizing heteromeric human P2X2/3 receptor. hP2X3 receptor desensitization was reversible and was not observed following the increase in intracellular Ca2+ levels produced by carbachol. A similar pattern of desensitization evoked by Ap5A was also observed using electrophysiological recordings of Xenopus oocytes expressing hP2X3 receptors. These data demonstrate that diadenosine polyphosphates, found endogenously in the central nervous system, can readily desensitize hP2X3 receptors at nanomolar concentrations that are 10-fold lower than are required to produce agonist-induced receptor activation. Thus, P2X3 receptor desensitization by diadenosine polyphosphates may provide an important modulatory mechanism of P2X3 receptor activation in vivo.


Mitochondrial DNA variations in ova and blastocyst: implications in assisted reproduction.
Mitochondrial DNA (mtDNA) of oocyte is critical for its function, embryo quality and development. Analysis of complete mtDNA of 49 oocytes and 18 blastocysts from 67 females opting for IVF revealed 437 nucleotide variations. 40.29% samples had either disease associated or non-synonymous novel or pathogenic mutation in evolutionarily conserved regions. Samples with disease associated mtDNA mutations had low fertilization rate and poor embryo quality, however no difference in implantation or clinical pregnancy rate was observed. Screening mtDNA from oocyte/blastocyst is a simple, clinically reliable method for diagnostic evaluation of female infertility and may reduce risk of mtDNA disease transmission.


The role of socio-demographic and health factors during COVID-19 in remote access to GP care in low-income neighbourhoods: a cross-sectional survey of GP patients.
Remote consultations were common in general practice during the COVID-19 pandemic. This approach may have affected access to GP care for people with low socio-economic status: this group has a high prevalence of chronic conditions and a higher mortality rate due to COVID-19. This study explores the association of sociodemographic and health factors with the decision to contact a GP practice, and care utilisation, among patients in low-income neighbourhoods in the Netherlands. Cross-sectional survey study. General practice in low-income neighbourhoods in the Netherlands. Patients from low-income neighbourhoods were selected from fourteen general practices on the basis of ethnic background, chronic disease or health literacy. Participants were stratified according to categories of these background characteristics to obtain equal numbers per category. A total of 213 surveys were retained for analysis. Need for GP contact, decision to contact a GP practice, and GP service utilisation. Forty-five percent (N = 88) of the participants experienced health problems for which they wished to consult their GP at the start of the outbreak of COVID-19. A majority of them (81%) had contact with a GP service. The need to contact the GP was significantly associated with financial difficulties (OR 2.20 CI (1.10 to 4.39)). An interaction effect was found of health literacy with concerns about COVID-19 with in respondents with low health literacy a significant association between concerns about COVID-19 and a need for a GP appointment (OR 5.33 CI (2.09 to 13.59)) and absence of a significant association in the higher health literacy group (OR 1.14 CI (0.51 to 2.56)) . Moreover, 56% (N = 74) of the participants received remote care at least one time during the first wave of COVID-19. Female participants used remote care more often (OR 3.22 CI (1.57 to 6.59)) and participants aged 50 and over used remote care less often (OR 0.46 CI (0.21 to 0.97)). Many patients in low-income neighbourhoods were able to consult a GP, often remotely. However from the equity perspective, access to GP care should be safeguarded for patients with health problems, financial difficulties and low health literacy because of their greater need to consult a GP during times of crisis.


Influence of probiotics on biofilm formation and diversity of bacteria colonising crop sorghum ensiled with unsalable vegetables.
The objective of this study was to characterise in situ digestion kinetics and bacterial colonisation of crop sorghum ensiled with unsalable carrot or pumpkin at 0, 20 or 40% dry matter (DM). Silages with or without the application of a commercial probiotic were incubated in situ for 0, 3, 6, 9, 24 and 48 h. Calculation of in situ digestion kinetics was conducted for DM, organic matter and neutral detergent fibre (aNDF). The V4 region of the 16S rRNA gene was sequenced to determine the composition and diversity of bacteria colonising the silage. Organic matter and DM digestion kinetics indicated that greater vegetable inclusion increased (P < 0.05) the soluble fraction and effective degradability. Bacterial richness at 48 h incubation was greater (P = 0.02) in 20% carrot and 40% pumpkin treatments, compared with the control. An effect of level × probiotic was observed with increased Shannon diversity (P = 0.01) for 40% carrot and 20% pumpkin probiotic treatments, respectively. Primary colonising bacteria were members of the Prevotella genus, dominating after 3 and 6 h of incubation. The abundance of Prevotella increased by 4.1% at 3 h (P < 0.01) and by 4.7% at 9 h incubation with probiotics, compared with the control. Secondary biofilm colonisers included members of Treponema, Saccharofermentans, Fibrobacter, Ruminobacter and Anaerosporobacter genera, dominant from 9 h incubation onward. This study demonstrated that including unsalable vegetables at 20 or 40% DM increases the soluble fraction and effective degradability of sorghum silage during in situ digestion and increases diversity of bacteria colonising ensiled vegetables within the rumen. KEY POINTS: • Ensiling unsalable vegetables is a viable strategy to reduce food waste. • Ensiled vegetables increased in situ soluble fraction and effective degradability. • Bacterial richness at 48 h incubation improved with 20% carrot or 40% pumpkin. • Diversity of colonising rumen bacteria increased with carrot or pumpkin inclusion.


Validation and adaptation of the empirical dietary inflammatory pattern across nations: A test case.
The empirical dietary inflammatory pattern (EDIP) assesses the inflammatory potential of diet in the US population. The aim of this study was to assess the applicability of the EDIP to a Brazilian population. Data from 19- to 75-y-old participants of two editions of the cross-sectional population-based Health Survey of Sao Paulo (HS-SP) were used to validate the EDIP (n = 269; HS-SP 2008), develop an EDIP adapted to a Sao Paulo population, the EDIP-SP (n = 441; HS-SP 2008), and replicate EDIP-SP results in an independent sample (n = 501; HS-SP 2015). Dietary data was assessed through two 24-h recalls and one validated food frequency questionnaire. Plasma C-reactive protein (CRP), and nine other inflammatory biomarkers were determined. EDIP was tested for its association with the 10 inflammatory biomarkers. For development of the EDIP-SP, 21 food groups and their contributions to plasma CRP levels were modeled using a stepwise multiple linear regression adjusted for age and sex. The EDIP was not associated with concentrations of inflammatory biomarkers in a Brazilian population. The components of EDIP-SP were processed meats (β = 0.27; P = 0.082), fruits and vegetables (β = -0.12; P = 0.018), and rice and beans (β = -0.27; P = 0.007). EDIP-SP significantly predicted dietary quality (β = -6.1; P < 0.001) and its inflammatory potential was replicated among men (β = 0.36; P = 0.01), but not among women (β = 0.05; P = 0.82). EDIP was adapted to the Sao Paulo population. EDIP-SP, composed of high processed meat intake and low intake of fruits and vegetables, and rice and beans, constitutes an important tool to investigate dietary quality based on its inflammatory potential, in Brazilian populations.


Molecular surveillance of methicillin-resistant Staphylococcus aureus genomes in hospital unexpectedly reveals discordance between temporal and genetic clustering.
The objective of this study was to identify sources and linkages among methicillin-resistant Staphylococcus aureus infections using whole-genome sequencing (WGS). A total of 56 samples were obtained from all patients with a confirmed MRSA infection over 6 months at University of Florida-Health Jacksonville. Samples were cultured and sequenced; data was analyzed on an automated cloud-based platform. Genetic Clusters were defined as <40 single nucleotide polymorphisms. Temporal Clusters were defined as ≥5 MRSA cases over 3 days. We found 7 Genetic Clusters comprising 15 samples. Four Genetic Clusters contained patients with non-overlapping stays (3-10 weeks apart), 3 of which contained patients who shared the same Unit. We also found 5 Temporal Clusters comprising 23 samples, although none of the samples were genetically related. Results showed that temporal clustering may be a poor indicator of genetic linkage. Shared epidemiological characteristics between patients in Genetic Clusters may point toward previously unidentified hospital sources. Repeated observation of related strains is also consistent with ongoing MRSA transmission within the surrounding high-risk community. WGS is a valuable tool for hospital infection prevention and control.


Comparison of laparoscopy-assisted partial nephrectomy using digital compression versus purely laparoscopic nephrectomy using vascular pedicle clamp in a porcine model.
Laparoscopic partial nephrectomy raises a number of technical issues, particularly in the control of bleeding. We compared digital compression during hand assistance with a vascular clamp. Laparoscopic transperitoneal bilateral lower-pole partial nephrectomy was performed on six pigs, with a vascular clamp being used on one side and digital pressure through an Omniport or Lapdisk on the other. The pigs were then euthanized and the kidneys harvested for histologic examination. Good hemostasis was obtained regardless of the technique. However, the estimated blood loss was significantly greater with digital compression (96.7 versus 9.6 mL). There were no significant micropathological differences in the kidneys. The surgeons rated suture tying and placement much easier with the purely laparoscopic technique. Both techniques are feasible. In experienced hands, the purely laparoscopic technique takes no longer than the hand-assisted technique and is associated with less blood loss, easier suturing, and better cosmesis. However, long-term follow-up is needed before clinical use can be contemplated.


Beyond the Categorical Distinction Between Borderline Personality Disorder and Bipolar II Disorder Through the Identification of Personality Traits Profiles.
The relationship between borderline personality disorder (BPD) and type-II bipolar disorder (BDII) is not clearly understood. Nevertheless, in clinical practice and research, most efforts focus on establishing a categorical distinction between the two. We propose using personality traits as a more informative strategy to describe them. Five-Factor Model personality traits were measured in 73 individuals with either BPD or BDII. Latent class cluster analysis was applied to the sample. A three-cluster model resulted the best fit to the data, where all clusters had high neuroticism and low extraversion scores but differed widely on the other traits. The clusters' boundaries did not match the categorical diagnosis. Our sample showed significant heterogeneity on personality traits, which can have a relevant effect on the outcome of each disorder and that was not captured by the categorical diagnosis. Thus, we advocate for a multivariate approach as a better way to understand the relationship between BPD and BDII.


An application for impedance spectroscopy in the characterisation of the glass transition during the lyophilization cycle: the example of a 10% w/v maltodextrin solution.
Impedance spectroscopy has been used for the measurement of the glass transition of a 10 % maltodextrin solution contained within a glass vial, with externally attached electrodes. Features of the pseudo-relaxation process, associated with the composite impedance of the glass vial-solution assembly, were characterised by the peak amplitude, C(peak)(″), and peak frequency, f(peak), of the capacitance spectra and the equivalent circuit elements that model the impedance spectra (i.e. the solution resistance and solution capacitance) and monitored every 3 min during re-heating of the solution. The time derivatives of all four parameters studied provided a glass transition in close agreement with DSC measurements (-17 °C) and at a precision of ± 0.5 °C. The temperature dependencies of the solution resistance and peak frequency were then characterised with the Arrhenius and Vogel-Fulcher-Tammann fit functions, at temperatures below and above Tg, respectively. The energy of activation (below Tg) was estimated at ~20 kJ mol(-1), and the fragility index (If) of the glass forming liquid (above Tg) was estimated at 0.9. The significance of the fragility index to the development, optimisation and control of the freeze-drying cycle is highlighted.


Legal claims in Scottish National Health Service Dermatology Departments 1989-2001.
An area of current National Health Service (NHS) interest is risk management as it is one of the requirements of clinical governance. If there are aspects of dermatological practice prone to mishap or dispute then a review of legal claims in dermatology may highlight these areas. This would then allow input into these specific areas of practice to try and minimize future risk. To review all legal claims relating to NHS Dermatology in Scotland and characterize the main areas of risk. Staff at the Central Legal Office in Edinburgh reviewed all legal claims in NHS Dermatology between 1989 and 2001. Details provided were general, and claimants, staff, hospitals and regions of Scotland could not be identified. Thirty claims were identified relating to five main areas of dermatological practice: (i) phototherapy (eight claims); (ii) therapeutics (eight); (iii) cryosurgery/cryotherapy (six); (iv) surgery (four); and (v) misdiagnosis (three) and one alleged neurological problem after fainting. As well as consultants, nurses featured in phototherapy claims and junior medical staff in cryosurgery claims. Twelve of the 30 (40%) claims have reached settlement; three claims are presently outstanding. Given the numbers of patients seen annually at Scottish NHS Hospital Dermatology units the absolute number of claims is low. Five main areas within dermatology were highlighted as at risk of litigation and this has implications for all U.K. dermatology departments with regard to funding, staff training and patient information and consent.


Surgical anatomy of left ventricular outflow tract obstruction in complete atrioventricular septal defect. A concept for operative repair.
An integral part of the heart with an atrioventricular septal defect and a Rastelli type A valve configuration is left ventricular outflow tract obstruction. Current surgical techniques do not cater to this particular anatomic facet, and left ventricular outflow tract obstruction has been reported as a postoperative problem. The present study has focused on the surgical anatomy of the mode of attachment of the left superior atrioventricular valve and its relationship to the left ventricular outflow tract. It appeared that the anchoring of the superior leaflet was a major factor in limiting the excursions of the superior leaflet, contributing also to the tightness of the subaortic left ventricular outflow channel. On that basis a surgical repair is proposed in which the greater part of the tightly bound superior leaflet is detached from the septal crest, so that the left ventricular outflow tract is widened.


Detection of Chlamydia pneumoniae and Helicobacter pylori in atherosclerotic plaques of carotid artery by polymerase chain reaction.
A possible role of some microorganisms has been proposed in the pathogenesis of atherosclerosis, but it is still an unresolved issue. We investigated the presence of Chlamydia pneumoniae and Helicobacter pylori DNA in carotid artery atherosclerotic plaques by using PCR. One hundred and four patients with atherosclerotic diseases were included. The study group consisted of 52 atherosclerotic plaque specimens obtained from the carotid arteries of patients who had carotid endarterectomy and the control group consisted of 52 specimens obtained from the macroscopically healthy regions of ascending aorta in patients who had undergone coronary artery bypass grafting. The presence of C. pneumoniae and H. pylori DNA in endarterectomy specimens were demonstrated by PCR. C. pneumoniae DNA was detected in 16 of 52 (30.8%) atherosclerotic plaques and 1 of 52 (1.9%) macroscopically healthy ascending aorta wall specimens (P < 0.001). H. pylori DNA was detected in 9 of 52 (17.3%) atherosclerotic plaques and none of the controls (P = 0.003). The higher incidence of C. pneumoniae and H. pylori DNA in atherosclerotic plaques suggests that these microorganisms may play a role in the pathogenesis of atherogenesis.


Circadian rhythms in mouse epidermal basal cell proliferation. Variations in compartment size, flux and phase duration.
Several kinetic parameters of basal cell proliferation in hairless mouse epidermis were studied, and all parameters clearly showed circadian fluctuations during two successive 24 hr periods. Mitotic indices and the mitotic rate were studied in histological sections; the proportions of cells with S and G2 phase DNA content were measured by flow cytometry of isolated basal cells, and the [3H]TdR labelling indices and grain densities were determined by autoradiography in smears from basal cell suspensions. The influx and efflux of cells from each cell cycle phase were calculated from sinusoidal curves adapted to the cell kinetic findings and the phase durations were determined. A peak of cells in S phase was observed around midnight, and a cohort of partially synchronized cells passed from the S phase to the G2 phase and traversed the G2 phase and mitosis in the early morning. The fluctuations in the influx of cells into the S phase were small compared with the variations in efflux from the S phase and the flux through the subsequent cell cycle phases. The resulting delay in cell cycle traverse through S phase before midnight could well account for the accumulation of cells in S phase and, therefore, also the subsequent partial synchrony of cell cycle traverse through the G2 phase and mitosis. Circadian variations in the duration of the S phase, the G2 phase and mitosis were clearly demonstrated.


Influence of Fatigue Loading and Bone Turnover on Bone Strength and Pattern of Experimental Fractures of the Tibia in Mice.
Bone fragility depends on bone mass, structure, and material properties, including damage. The relationship between bone turnover, fatigue damage, and the pattern and location of fractures, however, remains poorly understood. We examined these factors and their integrated effects on fracture strength and patterns in tibia. Adult male mice received RANKL (2 mg/kg/day), OPG-Fc (5 mg/kg 2×/week), or vehicle (Veh) 2 days prior to fatigue loading of one tibia by in vivo axial compression, with treatments continuing up to 28 more days. One day post fatigue, crack density was similarly increased in fatigued tibiae from all treatment groups. After 28 days, the RANKL group exhibited reduced bone mass and increased crack density, resulting in reduced bone strength, while the OPG-Fc group had greater bone mass and bone strength. Injury repair altered the pattern and location of fractures created by ex vivo destructive testing, with fractures occurring more proximally and obliquely relative to non-fatigued tibia. A similar pattern was observed in both non-fatigued and fatigued tibia of RANKL. In contrast, OPG-Fc prevented this fatigue-related shift in fracture pattern by maintaining fractures more distal and transverse. Correlation analysis showed that bone strength was predominantly determined by aBMD with minor contributions from structure and intrinsic strength as measured by nanoindentation and cracks density. In contrast, fracture location was predicted equally by aBMD, crack density and intrinsic modulus. The data suggest that not only bone strength but also the fracture pattern depends on previous damage and the effects of bone turnover on bone mass and structure. These observations may be relevant to further understand the mechanisms contributing to fracture pattern in long bone with different levels of bone remodeling, including atypical femur fracture.


Sinus versus nonsinus tachycardia in the emergency department: importance of age and heart rate.
The emergency department diagnosis of sinus versus nonsinus tachycardia is an important clinical challenge. The objective of this study was to identify subjects with a high prevalence of nonsinus tachycardia. Heart rate and cardiac rhythm were prospective reviewed in 500 consecutive patients with heart rate > or = 100 beats/min in a busy emergency department. A predictive model based on age and heart rate was then developed to identify the probability of nonsinus tachycardia. As age and heart rate increased, nonsinus tachycardias became more frequent. The probability of nonsinus tachycardia in a subject > or = 71 years with heart rate > or = 141 beats/minute was 93%, compared to only three percent in a subject < or = 50 years with heart rate 100-120 beats/minute. A simple point score system based on age and heart rate helps predict the probability of sinus tachycardia versus nonsinus tachycardia. Nonsinus tachycardia is significantly more common than sinus tachycardia in elderly patients in the emergency department. The diagnosis of sinus tachycardia becomes much less likely as age and heart rate increase.


A dual-institutional study on first-year practice outcomes of pediatric surgeons who trained in the era of work hour restrictions.
In July 2003, an 80-h work week restriction for residencies was mandated. This was met with skepticism regarding its potential impact on operative training. We hypothesized no difference in outcomes for pediatric surgeons who trained under duty hour restrictions compared to historical complication rates. Dual-institutional review of pediatric patients who underwent five of the most common operations (2013-2018) by first-year pediatric surgeons who trained under duty hour restrictions was performed. Tests of proportions were used to compare complication rates to published rates on data collected prior to 2003. Patient mean age was 10.1 years. No significant differences (p values > 0.05) were found in laparoscopic appendectomy rates of infection, bleeding or intra-abdominal abscess compared to previously published rates. Pyloromyotomy rates of infection or duodenal perforation were not different. No differences were detected in rates of infection, recurrence or testicular atrophy for inguinal hernia repair. Umbilical hernia rates of infection, bleeding, and recurrence were also not different. There was no difference in CVC rates of hemopneumothoraces; significantly more bleeding events were detected (1.2% vs. 0.1%; p value = 0.04). In this study, first-year complication rates of pediatric surgeons who trained under duty hour restrictions were not significantly different when compared to published rates.


Diagnostic and therapeutic problems in a case of adrenal tuberculosis and acute Addison's disease.
A case of adrenal tuberculosis with acute Addison's disease is presented. The case showed diagnostic and therapeutic problems, the latter concerning the untoward effects due to metabolic interferences and pharmacologic interactions among antitubercular drugs, substitutive corticosteroid therapy and hepatic metabolism. The side-effects, interactions and metabolism of drugs used during the course of disease are discussed.


[Genetic analysis of inheritance of mei8, sy1 and sy10 mutations, disrupting the correct meiosis in the rye Secale cereale L].
It is shown that mutations mei8 (irregular condensation and fragmentation of meiotic chromosomes), sy1 (asynapsis), and sy10 (heterologous synapsis) of rye Secale cereal are nonallelic. In double mutants mei8 sy1 and mei8 sy10 both mutations are expressed simultaneously and independently of each other. A study of joint inheritance of mutations sy1 and sy10 revealed their interaction by means of recessive epistasis: the double mutants has the sy10 phenotype. This means that the sy10 gene controls an earlier stage of synapsis in meiotic prophase than the sy1 gene. Mutation mei8 is inherited independently of sy1 but it is linked to sy10 (recombination frequency 26.8 +/- 3.58%).


Cytosolic location of an endo-N-acetyl-beta-D-glucosaminidase activity in rat liver and kidney.
Endo-N-acetyl-beta-D-glucosaminidase activity towards an oligomannosidic type glycoamino acid substrate was found in the soluble fraction of rat liver and kidney. No evidence for a lysosomal form of the activity was found.


Acute kidney injury and it's outcome following maternal near miss event: A prospective observational study from a tertiary care hospital.
Haemorrhage, preeclampsia and sepsis are the leading causes of renal dysfunction in women with a maternal nearmiss(MNM) complication. The study aimed to assess the prevalence, pattern and follow up of these women. This was a hospital based prospective observational study, conducted over one year. All women with a MNM leading to acute kidney injury (AKI) were analysed for fetomaternal outcomes and renal function at 1 year of followup. The incidence of MNM was 43.04 per 1000 livebirths. 18.2% women developed AKI. 51.1% women developed AKI in the puerperal period. Most common cause of AKI was haemorrhage seen in 38.3% women. The majority of women had s.creatinine between 2.1 to 5 mg/dl and 44.68% required dialysis. 80.8% women recovered fully when the treatment was initiated within 24 h. One patient underwent renal transplant. Early diagnosis and treatment of AKI results in full recovery.


[The effect of the type of astigmatism on the incidence of myopia].
To determine whether and how with-the-rule, against-the-rule or oblique astigmatism influence the creation of myopia. A total of 167 people with myopia (117 women and 50 men) of the age between 12 and 51, were examined. The overall average age was 24. Routine ophthalmological examinations as well as autorefractometry were carried out. The data was analysed using the coefficients of rang Spearman's correlation. It was found that with the rise of with-the-rule astigmatism myopia increases (P < 0.000001). Any correlation between the people with low, medium, and high myopia and the against-the-rule as well as oblique astigmatism was not observed. (1) With-the-rule astigmatism predisposes the creation of myopia. (2) Against-the-rule as well as oblique astigmatism has no influence on the creation of myopia.


International development and validation of a classification system for the identification of Barrett's neoplasia using acetic acid chromoendoscopy: the Portsmouth acetic acid classification (PREDICT).
Barrett's oesophagus is an established risk factor for developing oesophageal adenocarcinoma. However, Barrett's neoplasia can be subtle and difficult to identify. Acetic acid chromoendoscopy (AAC) is a simple technique that has been demonstrated to highlight neoplastic areas but lesion recognition with AAC remains a challenge, thereby hampering its widespread use. To develop and validate a simple classification system to identify Barrett's neoplasia using AAC. The study was conducted in four phases: phase 1-development of component descriptive criteria; phase 2-development of a classification system; phase 3-validation of the classification system by endoscopists; and phase 4-validation of the classification system by non-endoscopists. Phases 1 and 2 led to the development of a simplified AAC classification system based on two criteria: focal loss of acetowhitening and surface patterns of Barrett's mucosa. In phase 3, the application of PREDICT (Portsmouth acetic acid classification) by endoscopists improved the sensitivity and negative predictive value (NPV) from 79.3% and 80.2% to 98.1% and 97.4%, respectively (p<0.001). In phase 4, the application of PREDICT by non-endoscopists improved the sensitivity and NPV from 69.6% and 75.5% to 95.9% and 96.0%, respectively (p<0.001). We developed and validated a classification system known as PREDICT for the diagnosis of Barrett's neoplasia using AAC. The improvement seen in the sensitivity and NPV for detection of Barrett's neoplasia in phase 3 demonstrates the clinical value of PREDICT and the similar improvement seen among non-endoscopists demonstrates the potential for generalisation of PREDICT once proven in real time.


Sequential mediastinal lymphadenectomy of an unknown primary tumor.
An 83-year-old woman was admitted for lower mediastinal lymphadenopathy, detected by computed tomography; preoperative examinations did not detect a primary lesion. Fifteen months after tumor resection, a new mediastinal lymphadenopathy located 4 cm from the site of the first lesion was resected. Histopathologic and immunohistochemical examinations of both tumors revealed metastatic, poorly differentiated, adenocarcinomas with identical findings; however, the primary site could not be identified based on these examinations. The patient has remained disease-free for 23 months since the last surgery. Thus, sequential resections of metachronous mediastinal lymph node metastases from an unknown primary cancer yielded beneficial disease control.


A technique for measuring hepatic blood flow and oxygen consumption in the anaesthetised pig.
A technique for implanting a catheter in the hepatic vein of anaesthetised pigs is described. Hepatic blood flow (mean 1100 ml/min +/- 180 ml/min SEM) was estimated by the hepatic uptake of indocyanine green and the oxygen consumption by the liver (mean 62 ml/min +/- 3.4 ml/min SEM) was calculated from the difference in oxygen content between arterial and hepatic venous blood.


A multicenter retrospective cohort study on predicting the risk for amiodarone pulmonary toxicity.
Amiodarone is one of the most commonly used anti-arrhythmic agents. Amiodarone pulmonary toxicity is a potentially fatal adverse effect associated with amiodarone use. Previous studies on the epidemiology and risk factors for amiodarone pulmonary toxicity showed diverse results. A multicenter retrospective cohort study was conducted to identify clinic-epidemiologic markers associated with amiodarone pulmonary toxicity for development of a prediction rule. Patients taking amiodarone who were managed in 3 centres in Hong Kong from 2005 to 2015 were included in this study. Penalized logistic regression was used to model the outcome as it is rare. A total of 34 cases with amiodarone pulmonary toxicity were identified among 1786 patients taking amiodarone for at least 90 days from 2005 to 2015. The incidence of amiodarone pulmonary toxicity was estimated to be 1.9%. The risk factors for amiodarone pulmonary toxicity included advanced age (OR 1.047, 95% CI 1.010-1.085, p = 0.013), ventricular arrhythmia (OR 2.703, 95% CI 1.053-6.935, p = 0.039), underlying lung disease (OR 2.511, 95% CI 1.146-5.501, p = 0.021) and cumulative dose of amiodarone (OR 4.762, 95% CI 1.310-17.309 p = 0.018). The incidence of amiodarone pulmonary toxicity in Chinese patients in Hong Kong is estimated to be 1.9% in this study. Age, underlying lung disease, ventricular arrhythmia and cumulative dose of amiodarone are associated with the development of amiodarone pulmonary toxicity. A prediction rule was developed to inform the risk of developing amiodarone pulmonary toxicity.


Acute liver failure induced by alcohol and paracetamol in an HCV-infected haemophiliac.
Paracetamol (acetaminophen) is frequently used by haemophiliacs in the management of acute or chronic pain, primarily due to its lack of adverse effects when taken at therapeutic doses. We describe acute hepatic and renal toxicity of paracetamol in a 36-year-old patient with haemophilia B, chronic hepatitis C and chronic alcohol abuse. Moderate doses of paracetamol (6 g/d for 4 d), taken with therapeutic intent, resulted in life-threatening organ dysfunction which gradually recovered with full supportive care.


The impact of CT scanning and ultrasonography on orbital diagnosis.
New methods of soft tissue imaging have revolutionised the investigation of the orbit. The impact of CT scanning and ultrasonography is considered in relationship to established techniques including angiography. The importance of plain X-ray examination and conventional tomography is stressed for the exclusion of non-orbital causes of exophthalmos. In the orbit CT scanning is the best method of establishing the presence of a mass lesion; ultrasonography is useful principally for the investigation of optic nerve problems. Venography is still required in most patients to diagnose and establish the extent of a venous malformation in the orbit; it also has an important part to play in the diagnosis of inflammatory processes. Carotid angiography is now only required in patients with highly vascular orbital tumours, or with suspected arteriovenous anomalies. Plain X-ray examination, CT scanning and venography are regarded as the dominant investigations with conventional tomography, ultrasound, and arteriography playing a subsidiary role.


Incidental detection of colorectal lesions by FDG PET/CT scans in melanoma patients.
Increased use of PET/CT scans in oncology patients has raised detection of Colorectal incidentalomas (CIs). The frequency and diagnostic outcomes of identifying these lesions in melanoma patients have not previously been studied. This studies primary objective was to determine the prevalence of CIs found on PET/CT scans in melanoma patients. The secondary objectives were to correlate the PET/CT findings with the pathology found at colonoscopy, and identify which patients were referred for colonoscopy. A retrospective analysis of patients identified from the prospectively collected research database of Melanoma Institute Australia. 2509 patients with melanoma underwent PET/CT scans between 2001 and 2013. The prevalence of CIs, the correlation of lesions, and the survival of patients who underwent colonoscopy versus patients who did not were analyzed. The prevalence of CIs in melanoma patients who had PET/CT scans was 3.2%. Forty-five of the 81 (56%) patients with CIs underwent colonoscopy. Of these, premalignant or malignant disease was found in 58%. Patients with previous metastatic melanoma were significantly less likely to be referred for colonoscopy. Patients undergoing colonoscopy had significantly better survival, as did those without previous distant metastases before the CIs were found, and those without any metastases at the time the CIs were found. These factors were not significant on multivariate analysis. The prevalence of incidental colorectal lesions identified on PET/CT scans in melanoma patients was found to be equivalent to that in the general cancer population. Patients undergoing colonoscopy had better survival than those who did not.


The ganglioside antigen G(D2) is surface-expressed in Ewing sarcoma and allows for MHC-independent immune targeting.
Novel treatment strategies are needed to cure disseminated Ewing sarcoma. Primitive neuroectodermal features and a mesenchymal stem cell origin are both compatible with aberrant expression of the ganglioside antigen G(D2) and led us to explore G(D2) immune targeting in this cancer. We investigated G(D2) expression in Ewing sarcoma by immunofluorescence staining. We then assessed the antitumour activity of T cells expressing a chimeric antigen receptor specific for G(D2) against Ewing sarcoma in vitro and in vivo. Surface G(D2) was detected in 10 out of 10 Ewing sarcoma cell lines and 3 out of 3 primary cell cultures. Moreover, diagnostic biopsies from 12 of 14 patients had uniform G(D2) expression. T cells specifically modified to express the G(D2)-specific chimeric receptor 14. G2a-28ζ efficiently interacted with Ewing sarcoma cells, resulting in antigen-specific secretion of cytokines. Moreover, chimeric receptor gene-modified T cells from healthy donors and from a patient exerted potent, G(D2)-specific cytolytic responses to allogeneic and autologous Ewing sarcoma, including tumour cells grown as multicellular, anchorage-independent spheres. G(D2)-specific T cells further had activity against Ewing sarcoma xenografts. G(D2) surface expression is a characteristic of Ewing sarcomas and provides a suitable target antigen for immunotherapeutic strategies to eradicate micrometastatic cells and prevent relapse in high-risk disease.


A qualitative analysis of barriers to opioid agonist treatment for racial/ethnic minoritized populations.
Clinical guidelines strongly recommend opioid agonist treatment (OAT) as first-line treatment for opioid use disorder (OUD). However, racial/ethnic minoritized patients are less likely to receive OAT compared to non-Hispanic White patients. Reasons for this treatment gap must be elucidated to address racial/ethnic disparities in OAT. Our objective is to evaluate perceptions of and barriers to OAT across racial/ethnic groups in individuals with OUD (not on OAT). This qualitative study used semi-structured telephone interviews of adult patients (n = 41) with OUD (not currently being treated with OAT) from the Boston area from September 2020 through February 2021. We developed a codebook through author consensus based on review of themes in initial transcripts. We performed qualitative thematic analysis of the transcripts. We evaluated patients' perceptions of treatment for OUD across the study population and analyzed differences and similarities in perceptions between racial and ethnic groups. Across all racial/ethnic categories in our sample, anticipated stigma was the most frequently reported barrier to OAT and most patients preferred non-OAT methods for treatment. Non-Hispanic White participants had more favorable opinions of OAT compared to racial/ethnic minoritized participants. Racial/ethnic minoritized participants reported social support as the main facilitator to addiction treatment, while non-Hispanic White participants reported self-motivation as the most important factor. Racial/ethnic minoritized participants preferred treatment for OUD via non-OAT treatments and their second most preferred option was residential treatment. Non-Hispanic White participants preferred naltrexone and their second most preferred option was non-OAT treatments. Racial/ethnic minoritized patients' preference for residential treatment and social support, along with their distrust of OAT, illustrates a desire for psychosocial and peer recovery-based care that addresses social determinants of health. Addiction specialists may improve engagement with and treatment of racial/ethnic minoritized groups with culturally tailored interventions for OUD that offer psychosocial treatment in combination with OAT, and by partnering with organizations with strong ties to racial/ethnic minoritized communities. This kind of response would reflect the structural and cultural humility that is needed to adequately address the OUD needs of these underserved populations.


A further case of monosomy 10qter.
A child with a terminal deletion of chromosome 10 (q26) is described. A comparison of the phenotypic and cytogenetic features is made in the five reported cases of monosomy 10qter. No phenotypic features are found sufficiently characteristic to delineate a syndrome. Enzymatic activities for PGAMA and GOT1 were normal.


Hook plate fixation for type II fractures of the lateral end of the clavicle.
Management of type II fractures of the lateral end of the clavicle is controversial. Different treatment options have been advocated with varying results. In this paper, we report the results of a group of 22 patients who underwent hook plate fixation for these fractures between 1997 and 2004. The mean follow-up was 39 months. There were 4 significant complications. Twenty-one patients regained their preinjury level of activity, and 19 patients were satisfied with their outcome. We recommend hook plate fixation as an acceptable alternative method for the treatment of type II fractures of the lateral end of the clavicle.


Construction of a high-resolution physical map of the approximate 1-Mb region of human chromosome 7q31.1-q31.2 harboring a putative tumor suppressor gene.
Reports of frequent loss of heterozygosity (LOH) of markers on human chromosome 7q in malignant myeloid disorders as well as breast, prostate, ovarian, colon, head and neck, gastric, pancreatic, and renal cell carcinomas suggest the presence of a tumor suppressor gene (TSG). Functional assays have demonstrated that the introduction of an intact copy of human chromosome 7 (hchr7) can restore senescence to immortalized human fibroblast cell lines having LOH of markers within 7q31-q32 and can inhibit the tumorigenic phenotype of a murine squamous cell carcinoma cell line. To facilitate the cloning of the putative TSG, we have constructed a high-resolution physical map of this region of hchr7, specifically that encompassing the markers D7S522 and D7S677 within 7q31.1-q31.2. By using a lower resolution yeast artificial chromosome-based map as a starting framework, we established complete clone coverage of the implicated critical region in bacterial-artificial chromosomes (BACs) and P1-derived artificial chromosomes (PACs). The resulting BAC/PAC-based contig map has provided suitable clones for the systematic sequencing of the entire interval. In addition, we have already identified 29 clusters of overlapping expressed-sequence tags (ESTs) and 4 known genes contained within these clones. Together, the physical map reported here coupled with the evolving sequence and gene maps should hasten the identification of the putative TSG residing within this region of hchr7.


Elderly patients with acute myeloid leukaemia: characteristics in biology, patients and treatment. Recommendations of the Working Group Geriatric Oncology of the German Society for Haematology and Oncology (DGHO), the Austrian Society for Haematology and Oncology (OGHO) and the German Society for Geriatrics (DGG).
While the incidence rate of acute myeloid leukaemia (AML) is increasing with the age of the patients, the 5-year-survival rates are decreasing in an age-dependent manner. Patients with AML are considered to be old when they have reached the age of 60. This consideration is due to patient- and disease-specific parameters, which reveal differences between older and younger patients with AML. Standard of therapy is a dose-intensive chemotherapy aiming at the induction of complete remission, followed by different kinds of post-remission therapies. A small percentage of patients can be cured by this approach. However, most patients will die within the first 2 years after diagnosis due to resistance or relapse of the disease or therapy-related complications. The improvements achieved in the treatment of patients with AML are mainly restricted to the group of younger patients. The small percentage of patients who are cured, and the high rate of treatment-related mortality in elderly patients with AML give rise to the question which patients benefit from a primarily curative approach, and which should be treated with a palliative approach. The value of a palliative approach has not yet been consistently assessed in clinical trials. Geriatric assessment will be an important tool in clinical trials for elderly patients with AML to be used in the decision making process. There is hope that new classes of drugs and treatment modalities such as inhibitors of signal transduction, monoclonal antibodies, inhibitors of angiogenesis, or allogenic blood stem cell therapy after non-myeloablative conditioning regimens will improve the therapy of elderly patients with AML in the near future.


Efficient and Short Method for Conjugation of 1-Nitro-9-Aminoacridine to Important Peptidyl Fragments by a Solid Support Synthesis.
The efficient and short techniques for conjugation of 9-aminoacridine with different peptidyl fragments are necessary for the development of active pharmaceutical ingredients (API). They need to be adopted to generate a new branch of acridine conjugates, enhancing their bioavailability for the examination in biological systems. The branch of developing acridine conjugates, built via different linkers and synthesized in this study, are expected as potential effective chemotherapeutics with dual mechanism of action. Recently, the methodology based on a solid-phase technique has been successfully demonstrated in preparing a number of promising compounds. However, the reaction conditions for amide bond formation between 1-nitro-9-aminoacridine and peptidyl fragments need to be optimized. In this study, the optimization of amide bond formation was demonstrated with the use of the solid-phase synthesis to build a new promising group of 1-nitro-9-aminoacridines conjugated to lactoferrin fragments via especially carboxy linker length.


Helix packing motif common to the crystal structures of two undecapeptides containing dehydrophenylalanine residues: implications for the de novo design of helical bundle super secondary structural modules.
De novo designed peptide based super secondary structures are expected to provide scaffolds for the incorporation of functional sites as in proteins. Self-association of peptide helices of similar screw sense, mediated by weak interactions, has been probed by the crystal structure determination of two closely related peptides: Ac-Gly1-Ala2-Delta Phe3-Leu4-Val5-DeltaPhe6-Leu7-Val8-DeltaPhe9-Ala10-Gly11-NH2 (I) and Ac-Gly1-Ala2-DeltaPhe3-Leu4-Ala5-DeltaPhe6-Leu7-Ala8-DeltaPhe9-Ala10-Gly11-NH2 (II). The crystal structures determined to atomic resolution and refined to R factors 8.12 and 4.01%, respectively, reveal right-handed 3(10)-helical conformations for both peptides. CD has also revealed the preferential formation of right-handed 3(10)-helical conformations for both molecules. Our aim was to critically analyze the packing of the helices in the solid state with a view to elicit clues for the design of super secondary structural motifs such as two, three, and four helical bundles based on helix-helix interactions. An important finding is that a packing motif could be identified common to both the structures, in which a given peptide helix is surrounded by six other helices reminiscent of transmembrane seven helical bundles. The outer helices are oriented either parallel or antiparallel to the central helix. The helices interact laterally through a combination of N--H...O, C--H...O, and C--H...pi hydrogen bonds. Layers of interacting leucine residues are seen in both peptide crystal structures. The packing of the peptide helices in the solid state appears to provide valuable leads for the design of super secondary structural modules such as two, three, or four helix bundles by connecting adjacent antiparallel helices through suitable linkers such as tetraglycine segments.


The fundamentals of mold-related illness: when to suspect the environment is making a patient sick.
Disorders related to indoor air quality have become a major concern for primary care physicians, who often are asked to evaluate patients whose symptoms may be caused or aggravated by indoor exposure to mold. In this article, we review the common types of indoor mold and discuss the management of mold exposure and related illnesses.


Metarhizium anisopliae blastospores are highly virulent to adult Aedes aegypti, an important arbovirus vector.
The use of entomopathogenic fungi (EPF) for the control of adult mosquitoes is a promising alternative to synthetic insecticides. Previous studies have only evaluated conidiospores against adult mosquitoes. However, blastospores, which are highly virulent against mosquito larvae and pupae, could also be effective against adults. Metarhizium anisopliae (ESALQ 818 and LEF 2000) blastospores and conidia were first tested against adult Aedes aegypti by spraying insects with spore suspensions. Blastospores were then tested using an indirect contact bioassay, exposing mosquitoes to fungus-impregnated cloths. Virulence when using blastospores suspended in 20% sunflower oil was also investigated. Female mosquitoes sprayed with blastospores or conidia at a concentration of 108 propagules ml-1 were highly susceptible to both types of spores, resulting in 100% mortality within 7 days. However, significant differences in virulence of the isolates and propagules became apparent at 107 spores ml-1, with ESALQ 818 blastospores being more virulent than LEF 2000 blastospores. ESALQ 818 blastospores were highly virulent when mosquitoes were exposed to black cotton cloths impregnated with blastospores shortly after preparing the suspensions, but virulence declined rapidly 12 h post-application. The addition of vegetable oil to blastospores helped maintain virulence for up to 48 h. The results showed that blastospores were more virulent to adult female Ae. aegypti than conidia when sprayed onto the insects or applied to black cloths. Vegetable oil helped maintain blastospore virulence. The results show that blastospores have potential for use in integrated vector management, although new formulations and drying techniques need to be investigated.


In-particle stem-loop RT-qPCR for specific and multiplex microRNA profiling.
Here we report a novel method of microRNA (miRNA) profiling with particle-based multiplex quantitative reverse transcription polymerase chain reaction (RT-qPCR). To achieve target-specific reaction in a particle, the stem-loop RT primer and forward primer for each target miRNA were chemically immobilized to the particle. Target-specific cDNA synthesis proceeds with the stem-loop RT primer and then qPCR subsequently proceeds with the forward primer to rapidly achieve a quantitative result. High-fidelity multiplex assay was also accomplished in a single PCR process by loading multiple particles for each specific miRNA. The method for primer supply in the particles, involving confinement of the target-specific RT and PCR primers in the matrix of particles, led to the reduction of nonspecific reactions and improved the selectivity of the miRNA assay while minimizing labor in a multiple target assay. Specifically, this particle-based assay enabled the differentiation of mature miRNA from precursor with selectivity of 270:1 in terms of amplification speed. This advanced method also showed good discrimination among highly homologous let-7 family members, with cross-reaction rates of less than 5%. We demonstrated a very simple process of five-plex miRNA profiling in total RNA, and the measured changes in expression level were consistent with those from a conventional singleplex method.


Associations between leptospiral infection and seropositivity in rodents and environmental characteristics in Argentina.
Our objective was to look for associations between leptospiral infection in rodents and selected environmental and rodent characteristics in Santa Fe, Argentina. Rodents (n = 214) were trapped alive from January 1998 to December 1999 in three environmental settings. Kidneys from 118 rodents were cultured and serum samples from 201 were processed by enzyme-linked immunosorbent assay (ELISA). Logistic regression was performed with ELISA seropositivity as the dependent variable and rodent characteristics were offered as independent variables. Overall prevalence of positive ELISA reactions was 42% (84/201). In urban areas, leptospiral isolations belonged to the Ballum serogroup; in natural corridors, they belonged to the Icterohaemorragiae serogroup. M. musculus (house mouse) was the most-frequently captured species and the predominant one in urban areas. Most isolates and seropositivity results were obtained on this species. Adults and subadults had higher seroprevalences than juvenile rodents. Oligoryzomys flavescens had higher seroprevalence than Akodon azarae, Mus musculus, Rattus rattus and Rattus norvegicus.


Neural, psychophysiological, and behavioral markers of fear processing in PTSD: a review of the literature.
As presently defined, post-traumatic stress disorder (PTSD) is an amalgam of symptoms falling into: re-experiencing of the trauma, avoidance of reminders of it, emotional numbing and hyperarousal. PTSD has a well-known proximate cause, commonly occurring after a life-threatening event that induces a response of intense fear, horror, and helplessness. Much of the advancement in understanding of the neurobiology of PTSD has emerged from conceptualizing the disorder as one that involves substantial dysfunction in fear processing. This article reviews recent knowledge of fear processing markers in PTSD. A systematic search was performed of reports within the specific three-year publication time period of January 2010 to December 2012. We identified a total of 31 studies reporting fear processing markers in PTSD. We further categorized them according to the following classification: (1) neural-activation markers (n=10), (2) psychophysiological markers (n=14), and (3) behavioral markers (n=7). Across most studies reviewed here, significant differences between individuals with PTSD and healthy controls were shown. Methodological, theoretical and clinical implications were discussed.


[Diagnosis and surgical treatment of functional disorders of the cardia in duodenal ulcer].
The article deals with the problem of the functional status of the cardia in duodenal ulcer. The cardial function was studied in 27 patients with complicated duodenal ulcer. The results make it possible to judge about the degree of manifestation of cardia insufficiency. While tackling the problem of a character of surgical intervention upon the duodenal ulcer cases it is necessary, in author's opinion, to take into consideration the results of the functional examination of the cardia.


Routes Obey Hierarchy in Complex Networks.
The last two decades of network science have discovered stunning similarities in the topological characteristics of real life networks (many biological, social, transportation and organizational networks) on a strong empirical basis. However our knowledge about the operational paths used in these networks is very limited, which prohibits the proper understanding of the principles of their functioning. Today, the most widely adopted hypothesis about the structure of the operational paths is the shortest path assumption. Here we present a striking result that the paths in various networks are significantly stretched compared to their shortest counterparts. Stretch distributions are also found to be extremely similar. This phenomenon is empirically confirmed on four networks from diverse areas of life. We also identify the high-level path selection rules nature seems to use when picking its paths.


Cost analysis of office-based and operating room procedures in rhinology.
Analyses of office-based procedures in laryngology and otology have shown them to be safe and satisfying for patients, with substantial savings of time and money for patients and physicians. The objectives of this study were to compare the billable charges and reimbursement for rhinologic procedures performed in the office with charges for procedures performed in an ambulatory surgery center operating room (OR). A retrospective, matched-pair cost analysis was performed. Patients who underwent office-based procedures between 2006 and 2011 were matched by Current Procedural Terminology® (CPT) code with patients who underwent similar procedures in the OR. Twenty-nine matched pairs were included. Charges for surgery, anesthesia, and facility usage were analyzed. Because surgery charges may be influenced by contracts with insurance providers, both the total billed charges and total allowed charges were analyzed using paired t tests. When a single office-based procedure was compared with multiple procedures performed during the same operation in the OR, anesthesia and facility charges were scaled to allow for more accurate comparison. Mean total charges for office-based procedures were significantly less than for OR procedures ($2,737.17 vs $7,329.69, p < 0.001). Mean allowed charges for office-based procedures were significantly less than for OR procedures ($762.08 vs $5,835.09, p < 0.001). Mean scaled charges for office-based procedures were also significantly less than mean scaled charges for OR procedures ($762.08 vs $4,089.33, p < 0.001). Office procedures were reimbursed at similar or higher rates than were OR procedures. In appropriate patients, performing simple rhinologic procedures in the office rather than in the OR offers significant cost savings without impacting physician reimbursement.


Longitudinal Assessment of a Manualized Group Treatment Program for Gambling Disorder: The Ohio Problem Gambling Treatment Model for Adults with Co-Occurring Disorders.
Individuals with gambling disorder (GD) experience a host of negative psychosocial and physical health outcomes, yet few seek treatment. Of particular concern are individuals with co-occurring mental and behavioral health disorders, a group at higher risk for GD in the state of Ohio. To better serve this population, the Ohio Department of Mental Health and Addiction Services developed a group-based GD treatment manual for adults with co-occurring disorders. Over the course of 5 years, 353 individuals engaged in at least some of the manual's 12 weekly modules, and more than one-third (n = 122) completed the entire curriculum. Participants who completed all 12 modules completed pre-and post-tests, and after controlling for covariates, participants significantly decreased their GD symptom severity, though changes in self-esteem and gambling urges were non-significant. These findings suggest the treatment manual holds promise at reducing gambling behaviors for individuals with co-occurring disorders, but further research is warranted to explore best practices on how to intervene on the psychological antecedents to gambling in this population.


Five-year mortality after acute poisoning treated in ambulances, an emergency outpatient clinic and hospitals in Oslo.
The long-term mortality after prehospital treatment for acute poisoning has not been studied previously. Thus, we aimed to estimate the five-year mortality and examine the causes of death and predictors of death for all acutely poisoned patients treated in ambulances, the emergency outpatient clinic, and hospitals in Oslo during 2003-2004. A prospective cohort study included all adults (≥16 years; n=2045, median age=35 years, male=58%) who were discharged after treatment for acute poisoning in ambulances, the emergency outpatient clinic, and the four hospitals in Oslo during one year. The patients were observed until the end of 2008. Standardized mortality rates (SMRs) were calculated and multivariate Cox regression analysis was applied. The study comprised 2045 patients; 686 treated in ambulances, 646 treated in the outpatient clinic, and 713 treated in hospitals. After five years, 285 (14%) patients had died (four within one week). The SMRs after ambulance, outpatient, and hospital treatment were 12 (CI 9-14), 10 (CI 8-12), and 6 (CI 5-7), respectively. The overall SMR was 9 (CI 8-10), while the SMR after opioid poisoning was 27 (CI 21-32). The most frequent cause of death was accidents (38%). In the regression analysis, opioids as the main toxic agents (HR 2.3, CI 1.6-3.0), older age (HR 1.6, CI 1.5-1.7), and male sex (HR 1.4, CI 1.1-1.9) predicted death, whereas the treatment level did not predict death. The patients had high mortality compared with the general population. Those treated in hospital had the lowest mortality. Opioids were the major predictor of death.


A conserved alternative form of the purple sea urchin HEB/E2-2/E2A transcription factor mediates a switch in E-protein regulatory state in differentiating immune cells.
E-proteins are basic helix-loop-helix (bHLH) transcription factors with essential roles in animal development. In mammals, these are encoded by three loci: E2-2 (ITF-2/ME2/SEF2/TCF4), E2A (TCF3), and HEB (ME1/REB/TCF12). The HEB and E2-2 paralogs are expressed as alternative (Alt) isoforms with distinct N-terminal sequences encoded by unique exons under separate regulatory control. Expression of these alternative transcripts is restricted relative to the longer (Can) forms, suggesting distinct regulatory roles, although the functions of the Alt proteins remain poorly understood. Here, we characterize the single sea urchin E-protein ortholog (SpE-protein). The organization of the SpE-protein gene closely resembles that of the extended HEB/E2-2 vertebrate loci, including a transcript that initiates at a homologous alternative transcription start site (SpE-Alt). The existence of an Alt form in the sea urchin indicates that this feature predates the emergence of the vertebrates. We present additional evidence indicating that this transcript was present in the common bilaterian ancestor. In contrast to the widely expressed canonical form (SpE-Can), SpE-Alt expression is tightly restricted. SpE-Alt is expressed in two phases: first in aboral non-skeletogenic mesenchyme (NSM) cells and then in oral NSM cells preceding their differentiation and ingression into the blastocoel. Derivatives of these cells mediate immune response in the larval stage. Inhibition of SpE-Alt activity interferes with these events. Notably, although the two isoforms are initially co-expressed, as these cells differentiate, SpE-Can is excluded from the SpE-Alt(+) cell population. This mutually exclusive expression is dependent on SpE-Alt function, which reveals a previously undescribed negative regulatory linkage between the two E-protein forms. Collectively, these findings reorient our understanding of the evolution of this transcription factor family and highlight fundamental properties of E-protein biology.


Race/ethnicity and sex in U.S. occupations, 1970-2010: Implications for research, practice, and policy.
We used census data on the civilian non-institutional adult population to analyze trends in labor force participation by race/ethnicity and sex in U.S. occupations from 1970 to 2010 in decennial periods. We examined these data for the main effects and interactions of race/ethnicity and sex across the total labor market and within 35 detailed occupations. Results from a log-linear analysis revealed that, as a whole (across race/ethnicity), more women participated in the labor force from 1970 to 2010. The proportions of working racial/ethnic minorities to both the population and the people in the labor force increased across all decades except for Black men. Although White (Caucasian) men continuously comprised the largest racial/ethnic-sex group working across five decades in absolute numbers, their percentage of the total working population declined from 1970 (54%) to 2010 (37%). In our analyses of 35 occupations, significant sex differences within racial/ethnic groups emerged. Overall, with some exceptions, Asian men and women and White women were more likely to be absorbed into occupations typically associated with professional status whereas Black, Hispanic, and American Indian men and women were more likely to be absorbed into occupations typically associated with low skill, low wages, and low status. Implications for the role of psychologists in future research, practice, and policy are discussed.


Employment functioning in people with severe mental illnesses living in urban vs. rural areas in India.
Research on employment in people with severe mental illnesses (SMI) in developing countries is sparse and largely limited to employment rates. We conducted a comprehensive study of work, interest in work, and perceived benefits and barriers to work in people with SMI in India. Semi-structured interviews were conducted with 550 individuals with SMI receiving private psychiatric outpatient services in two districts in western India, one urban (Pune) and the other rural (Ahmednagar). More than half of the participants were employed, with significantly more men working (79.4%) than women (35.9%). Higher rates of work were found in rural areas (77.8%), where most work was in family agricultural businesses, than in urban areas (48.9%), where most work was for independent employers. Participants in rural areas worked fewer hours and earned less money, and reported fewer benefits and fewer problems related to work than urban participants. Over 45% of participants working for independent employers found jobs with help from families and extended social networks. Most unemployed participants wanted to work, and desired a variety of supports, including assistance with job finding and illness management. Gender-specific social role expectations and families play an important role in work in people with SMI in India. Despite higher rates of work in this sample than most studies from developed countries, a significant subgroup was unemployed but wanted to work. Persons with SMI in developing countries may benefit from the adaptation of validated vocational rehabilitation approaches in developed countries to their cultural context.


[Contribution to the study of Microphallidae Travassos, 1920 (Trematoda). XXXIV. Redescription of Levinseniella howensis Johnston, 1917 (author's transl)].
According to the type of L. howensis the species belongs to the subgenus Levinseniella instead of the subgenus Monarrhenos as believed before. The genital atrium has two male pockets and one female pouch.


Lysophosphatidic acid signaling may initiate fetal hydrocephalus.
Fetal hydrocephalus (FH), characterized by the accumulation of cerebrospinal fluid, an enlarged head, and neurological dysfunction, is one of the most common neurological disorders of newborns. Although the etiology of FH remains unclear, it is associated with intracranial hemorrhage. Here, we report that lysophosphatidic acid (LPA), a blood-borne lipid that activates signaling through heterotrimeric guanosine 5'-triphosphate-binding protein (G protein)-coupled receptors, provides a molecular explanation for FH associated with hemorrhage. A mouse model of intracranial hemorrhage in which the brains of mouse embryos were exposed to blood or LPA resulted in development of FH. FH development was dependent on the expression of the LPA(1) receptor by neural progenitor cells. Administration of an LPA(1) receptor antagonist blocked development of FH. These findings implicate the LPA signaling pathway in the etiology of FH and suggest new potential targets for developing new treatments for FH.


Stereotactic single high dose radiation therapy of benign intracranial meningiomas.
Seventeen patients with intracranial meningiomas were treated with single high dose irradiation at the German Cancer Research Center in Heidelberg. Indications for radiosurgery included unresected tumors, gross disease remaining despite surgery, and recurrences. Therapy was carried out by a technique using multiple non-coplanar arc irradiations from a 15 MeV linear accelerator. This technique coupled with secondary tungsten collimators allowed a high concentration of the dose in the target volume with an extremely steep dose gradient at the field borders. The patients were treated with a single irradiation dose ranging from 10 to 50 Gy (mean of 29 Gy). Four of 17 patients died: one death was tumor-related and not attributable to the treatment, one died of a treatment related complication, and two patients died of intercurrent diseases. The remaining 13 of the 17 patients with a median follow-up time of 40 months have no evidence of tumor relapse. Late severe side effects include five patients with a large area of brain edema, three of which were concurred with tumor necrosis. We conclude from these initial data that single high doses of irradiation concentrated to the tumor volume by stereotaxic methods can achieve local tumor control. It is also clear from these data that the effective therapeutic dose range must be better defined.


Bisphosphonates reduce bone mineral loss at ligament entheses after joint injury.
To examine the effects of anterior cruciate ligament (ACL) insufficiency, and subsequent bisphosphonate (BP) antiresorptive therapy, on the bone mineral interface at the enthesis of remaining ligamentous restraints. We measured bone mineral geometry (and subsequent adaptation) at the medial collateral ligament (MCL) origin, using micro-computed tomography (muCT). Groups of normal control, 6 and 14 wk anterior cruciate ligament transected (ACLX), and 6 wk ACLX-BP (risedronate) dosed rabbits were evaluated. Samples were then processed histologically, and the results of mineral adaptation and progression of osteoarthritis (OA) compared to joint laxity values obtained from previous biomechanical testing of the MCL-complex. muCT defined the MCL origin as a symmetrical, metaphyseal depression that contained soft-tissue elements, including fibrocartilage and ligament--as seen in subsequent histological sections. In contrast, the insertions from ACLX animals lost significant bone mineral, with an MCL-insertion volume 1.2 times that of normal controls at 6 wk ACLX, which further increased to 2.3 times that of normal controls at 14 wk ACLX. Significant differences were also measured between 6 and 14 wk ACLX and age-matched normal controls in volume of cortical bone containing the MCL insertion. However, there were no significant differences in the percentage of cortical bone to underlying trabecular bone at the MCL insertion. When comparing muCT mineral adaptation at the MCL-enthesis with historical MCL-complex laxity data, the values for laxity after ACLX increased proportionately as bone mineral at the insertion was lost, and subsequent use of the BP risedronate reduced both mineral loss and MCL-complex laxity. Compared to the untreated ACLX condition, administering bisphosphonate immediately after loss of the ACL conserved bone mineral at the MCL enthesis, suggesting the potential to therapeutically influence joint-complex laxity and OA progression.


Methylprednisolone in neonatal cardiac surgery: reduced inflammation without improved clinical outcome.
Corticosteroids are widely used in pediatric open-heart surgery to reduce systemic inflammatory response and to mediate possible cardioprotective effects. However, the optimal dosing of corticosteroids is unknown and their administration varies considerably between different institutions. Forty neonates undergoing open-heart surgery were randomized in a double-blind fashion equally into 2 groups. After the induction of anesthesia, 1 group received 30 mg/kg intravenous methylprednisolone and the other a placebo. Concentrations in plasma of interleukin 6 (IL-6), IL-8, IL-10, free methylprednisolone and total methylprednisolone were obtained for the following: (1) at anesthesia induction before the study drug was administered; (2) 30 minutes on cardiopulmonary bypass; (3) 5 minutes after protamine administration; and (4) 6 hours after weaning from cardiopulmonary bypass. Troponin T was measured at time points T1, T3, T4, and also at 6:00 on the first postoperative morning. Physiological and clinical outcome parameters were also recorded. Intravenous methylprednisolone resulted in high plasma drug concentrations that peaked at T2. Methylprednisolone significantly lowered concentrations of proinflammatory cytokines IL-6 and IL-8 and raised levels of anti-inflammatory IL-10. No significant differences in troponin T levels were detected. Blood glucose levels were significantly higher in the methylprednisolone group, and patients in this group received more often insulin therapy than controls. No significant differences were observed in other clinical or physiological outcome measurements. Intravenous 30 mg/kg methylprednisolone administered before cardiopulmonary bypass resulted in high effective plasma drug concentrations and a decreased inflammatory response. However, no cardioprotective effect or better clinical outcome was noticed.


Efficacy and duration of botulinum toxin treatment for drooling in 131 children.
To address the efficacy of botulinum toxin and the duration of its effect when used on a large scale for the treatment of drooling in children with neurological disorders. Prospective cohort study. Academic multidisciplinary drooling clinic. A total of 131 children diagnosed as having cerebral palsy or another nonprogressive neurological disorder and who also have moderate to severe drooling. Injection of botulinum toxin to the submandibular glands. Direct observational drooling quotient (DQ) (0-100) and caretaker visual analog scale (VAS) scores (0-100). A clinically notable response was found in 46.6% of children, reflected in a significant mean reduction in DQ from a baseline of 29 to 15 after 2 months and 19 after 8 months (P < .001). The mean VAS score decreased from 80 at baseline to 53 after 2 months and increased to 66 after 8 months (P < .001). Kaplan-Meier analysis showed that patients who initially responded to treatment experienced relapse after a median of 22 weeks (interquartile range, 20-33 weeks). Our study provides further support for botulinum toxin's efficacy for treatment of drooling in approximately half of patients for a median of 22 weeks. Further optimization of patient selection should be an area of attention in future studies.


Microheterogeneity of serum alkaline phosphatase isoenzymes as revealed by isoelectric focusing.
The microheterogeneity of human serum alkaline phosphatase (ALP) was investigated by means of isoelectric focusing. Liver and bone isoenzymes focused in a similar pattern, with about 10 bands located between pH 3.7 and 4.9, but differed in the relative intensity of the various bands. Intestinal ALP exhibited 7 to 8 bands at pH 4.9-5.1, and the placental enzyme showed 2 to 3 bands at pH 4.9. Mild digestion with neuraminidase revealed that the banding of liver and bone isoenzymes was at least partly due to differences in the sialic acid content of the various fractions. Extensively desialylated liver and bone isoenzymes showed apparently identical patterns with 6 to 7 bands focused at pH 6.2-6.7. Isoelectric focusing is a useful method for characterizing the microheterogeneity of alkaline phosphatase isoenzymes. The clinical value of this method seems to be limited, however, since it did not distinguish between liver and bone isoenzymes and failed to detect 'specific' isoelectric fractions correlated to various diseases.


Promoting effect of pomegranate peel extract on second-degree burn wound-healing through VEGF-A and TGF-β1 regulation.
Pomegranate peel extract (PPE), a polyphenolic compound derived from pomegranate, has been widely concerned for its anti-oxidant, anti-inflammatory, and bacteriostatic effects. The potential therapeutic effect of PPE on burn injury was investigated, and its possible mechanisms were explored. Minipigs with second-degree burn were treated with PPE, Jing Wan Hong, and silver sulfadiazine. Hematoxylin-eosin (HE) staining was performed to detect burn severity, and then biological tissues were biopsied on days 0, 7, 14, 21, and 28 after administration. Immunohistochemistry, western blot, and real-time polymerase chain reaction (RT-PCR) were used to detect the protein and mRNA expression levels of VEGF-A and TGF-β1 in skin tissues after treatment with PPE. Furthermore, the skin wound healing at different time points was monitored by macroscopic observation. HE showed that after 28-day PPE treatment, the morphology of the skin tissue showed a significant improvement. Macroscopic data monitoring indicated that the decrustation and fur growing time was shortened. Meanwhile, the rate of wound healing increased after PPE treatment. The combination of immunohistochemistry, western blotting, and RT-PCR showed that after PPE treatment, expression of VEGF-A and TGF-β1 increased sharply on day 7, maintaining a high level until day 14, showing a downward trend on day 21, and approaching normal levels on day 28. However, in the model group, the protein and mRNA expression levels of VEGF-A and TGF-β1 increased on day 28 after burn injury, which was a slow process. Results indicated that compared with the model group, the peak expression level of VEGF-A and TGF-β1 was earlier, which was consistent with decrustation, shortening of fur growing time, and improvement of wound healing rate in minipig second-degree burn model. PPE showed a significant promoting effect on minipig second-degree burn model, which might be associated with the upregulation of the protein and gene expression levels of VEGF-A and TGF-β1.