Sequence analysis of the EF-1 alpha gene family of Mucor racemosus.
Our previous studies have shown that Mucor racemosus possesses three genes (TEF-1, -2 and -3) for EF-1 alpha, and that all three genes are transcribed. However, the level of transcription varies markedly between the three genes, with TEF-1 mRNA levels being approximately two fold higher than TEF-3 and 6 fold higher than TEF-2. We have now completed the DNA sequence of both strands of all three genes and have found that these genes are highly homologous. TEF-2 and TEF-3 are more similar to each other than they are to TEF-1. The TEF-2 and the TEF-3 coding regions differ from TEF-1 at 30 and 37 positions respectively out of 1374 nucleotides. Twenty-six of these nucleotide substitutions were common to both TEF-2 and TEF-3, and the majority of the substitutions were clustered in the 5' region of the coding sequences. While the majority of these changes were silent, TEF-2 and TEF-3 differed from TEF-1 by having a lysine instead of a glutamate at amino acid position 41. In addition, TEF-2 and -3, but not TEF-1, each have an intron located near the 5' end of the coding region, although its size and sequence is not conserved between the two genes. All three genes have a conserved intron near the 3' end of the coding region. The sequence data have been analyzed with respect to the structure and function of EF-1 alpha in protein biosynthesis.


Effect of tetrandrine on myocardial Na+, K(+)-ATPase in renovascular hypertensive rats.
In renovascular hypertensive rats (RVHR, two-kidney, one-clip model), the myocardial Na+, K(+)-ATPase showed a reduced activity. Though its sensitivities to K+ and ouabain (Oua) were not changed, the enzyme was less responsive to Na+ and ATP, and also much more susceptible to the inhibitory effect of Ca2+. Tetrandrine (Tet, ig 50 mg.kg-1, qd x 26 d) increased the myocardial Na+, K(+)-ATPase activity in RVHR. However, in vitro, Tet elevated moderately the enzyme activity in RVHR only at high concentrations (100-1,000 mumol.L-1), and failed to influence the enzyme activity in normotensive rats. In RVHR, treatment by Tet in vivo increased the degree of the Na+, K(+)-ATPase activation under suboptimal substrate (Na+, K+, or ATP) concentrations and antagonized the inhibitory effect of Ca2+ or Oua. Similar results were found when the enzyme preparation from RVHR was incubated with Tet 10 mumol.L-1 during ATPase analysis. On the contrary, the myocardial Mg(2+)-ATPase activity was higher in RVHR. Tet depressed this enzyme both in vivo and in vitro. These facts indicate that the increased myocardial Na+, K(+)-ATPase activity in RVHR is not only secondary to the calcium channel blocking or antihypertensive action of Tet but also due to its direct effects on the Na+, K(+)-ATPase and Mg(2+)-ATPase.


Modified PAP method to detect heteroresistance to vancomycin among methicillin resistant Staphylococcus aureus isolates at a tertiary care hospital.
This study was an attempt at developing, establishing, validating and comparing the modified PAP method for detection of hetero-vancomycin resistant Staphylococcus aureus (h-VRSA) with the routine antimicrobial susceptibility testing (using the BSAC standardized disc diffusion method), minimum inhibitory concentrations of vancomycin using standard E-test methodology and the Hiramatsu's screening method. A total of 50 methicillin resistant Staphylococcus aureus obtained from various clinical specimens, along with the Mu 3 and Mu 50 strains as controls, were studied. No VRSA isolates were obtained. However, four of the test strains were positive by the Hiramatsu's screening method, of which only one isolate could be confirmed by the modified PAP analysis method. This isolate was a coloniser from the drain fluid of a liver transplant recipient. The sensitivity, specificity, positive predictive value and the overall efficiency of the Hiramatsu's screening method with the modified PAP analysis as the gold standard were found to be 100, 93.8, 25 and 94%, respectively. It is very essential for clinical laboratories to screen for h-VRSA, given the increasing use of glycopeptide antibiotics in therapy and the potential for failed therapy in patients infected with these strains.


Reversible pulmonary hypertension associated with vitamin C deficiency.
We describe the case of a 40-year-old female patient who developed severe pulmonary hypertension and life-threatening right-sided heart failure in association with dietary scurvy and iron deficiency. Supplementation with oral vitamin C and iron very likely contributed to her complete cure. Scurvy-associated pulmonary arterial hypertension could result from impaired availability of endothelial nitric oxide, but inappropriate activation of the hypoxia-inducible family (HIF) of transcription factors could play an even more important role. HIF coordinates the body's responses to hypoxia, and its activity is regulated by oxygen-dependent prolyl hydroxylases, which need vitamin C and iron as cofactors. Deficiency of these cofactors could lead to uncontrolled HIF activity and pulmonary vasoconstriction responsive to vitamin C and iron administration.


Differential regulation of AMP-activated protein kinase in healthy and cancer cells explains why V-ATPase inhibition selectively kills cancer cells.
The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic hub regulating various pathways involved in tumor metabolism. Here we report that vacuolar H+-ATPase (V-ATPase) inhibition differentially affects regulation of AMPK in tumor and nontumor cells and that this differential regulation contributes to the selectivity of V-ATPase inhibitors for tumor cells. In nonmalignant cells, the V-ATPase inhibitor archazolid increased phosphorylation and lysosomal localization of AMPK. We noted that AMPK localization has a prosurvival role, as AMPK silencing decreased cellular growth rates. In contrast, in cancer cells, we found that AMPK is constitutively active and that archazolid does not affect its phosphorylation and localization. Moreover, V-ATPase-independent AMPK induction in tumor cells protected them from archazolid-induced cytotoxicity, further underlining the role of AMPK as a prosurvival mediator. These observations indicate that AMPK regulation is uncoupled from V-ATPase activity in cancer cells and that this makes them more susceptible to cell death induction by V-ATPase inhibitors. In both tumor and healthy cells, V-ATPase inhibition induced a distinct metabolic regulatory cascade downstream of AMPK, affecting ATP and NADPH levels, glucose uptake, and reactive oxygen species production. We could attribute the prosurvival effects to AMPK's ability to maintain redox homeostasis by inhibiting reactive oxygen species production and maintaining NADPH levels. In summary, the results of our work indicate that V-ATPase inhibition has differential effects on AMPK-mediated metabolic regulation in cancer and healthy cells and explain the tumor-specific cytotoxicity of V-ATPase inhibition.


Anticancer efficacy of deguelin in human prostate cancer cells targeting glycogen synthase kinase-3 β/β-catenin pathway.
Activation of survival pathways has been associated with chemoresistance and progression of androgen independence which places a major obstacle to successful treatment of metastatic prostate cancer. Deguelin, a rotenoid isolated from Mundulea sericea, has an anticancer effect against several types of cancers; however, the mechanism of its antitumor effects on prostate cancer is not well understood. The aim of our study was to elucidate the effect of deguelin on the growth of prostate cancer cells and its putative mechanism of action. Deguelin decreased the viability of both androgen-dependent and -independent prostate cancer cells but not normal prostate epithelial cells. Downregulation of phosphorylated Akt and GSK-3β by deguelin promoted proteosomal degradation of β-catenin that resulted in decreased nuclear accumulation and inhibited transactivation of β-catenin-responsive genes. Deguelin-induced downregulation of proliferative (cyclin D1 and c-myc) and antiapoptotic proteins (Mcl-1, Bcl-xL and survivin) in prostate cancer cells culminated in the induction of apoptosis, inhibition of DNA synthesis and cell growth, altered membrane integrity, marked reduction of invasiveness, inhibition of anchorage-dependent and -independent colony formation. Our data demonstrated for the first time that deguelin inhibits the growth and survival of human androgen-independent prostate cancer cells, and its anticancer and antimetastatic activity occurs, at least in part through downregulating GSK-3β/β-catenin signaling pathway and antiapoptotic survival proteins. Taken together our study indicates that deguelin may have translational potential as therapeutic agent for advanced or metastatic prostate cancer.


Behavior and development of preschool children born to adolescent mothers: risk and 3-generation households.
To investigate whether living in a 3-generation household (grandmother-mother-child) is associated with fewer behavior problems and better cognitive development among preschool children of mothers who gave birth during adolescence and whether it protects children from the behavior and developmental problems associated with maltreatment and maternal depression. Cohort study. Participants included low-income families recruited from 4 sites: East, Northwest, Midwest, and South, who are part of LONGSCAN, a longitudinal study of children's health, development, and maltreatment. One hundred ninety-four mothers who were adolescents (less than age 19) at delivery. Data were gathered when children were 4 to 5 years of age. Twenty-six percent of the children lived in 3-generation households, 39% had a history of maltreatment, and 32% of the mothers had depression scores in the clinical range. Child behavioral problems were measured with the Child Behavior Checklist, completed by the mother, and child developmental status was assessed with the Battelle Developmental Inventory Screening Test, administered by research assistants. Multiple regression analyses revealed that children who had been reported for maltreatment and had mothers with depressive symptoms had more externalizing behavior problems, compared with children who experienced neither risk or only 1 risk. However, when residential status was considered, children with the greatest number of externalizing behavior problems were those who experienced both maltreatment and maternal depressive symptoms and lived in 3-generation households. Children who had been reported for maltreatment or had mothers with depressive symptoms were more likely to have internalizing problems, compared with children with neither risk. Residential status was not related to children's internalizing behavior problems or cognitive development. Living in a 3-generation household did not protect preschool children from the behavior problems associated with maltreatment and depression. In contrast, living in a 3-generation household was associated with more behavior problems among the highest risk group of children--those who had been maltreated and had mothers with symptoms of depression. Although 3-generation families may provide an important source of support and stability for adolescent mothers and their infants early in the parenting process, it may not be advisable to rely on 3-generation households as young mothers enter adulthood, particularly among those with a history of maltreatment or depression. Children with the fewest number of behavior problems were living with their mothers in their own household (often with the father), had not been maltreated, and had mothers with few symptoms of depression.


Mathematical prognostic biomarker models for treatment response and survival in epithelial ovarian cancer.
Following initial standard chemotherapy (platinum/taxol), more than 75% of those patients with advanced stage epithelial ovarian cancer (EOC) experience a recurrence. There are currently no accurate prognostic tests that, at the time of the diagnosis/surgery, can identify those patients with advanced stage EOC who will respond to chemotherapy. Using a novel mathematical theory, we have developed three prognostic biomarker models (complex mathematical functions) that-based on a global gene expression analysis of tumor tissue collected during surgery and prior to the commencement of chemotherapy-can identify with a high accuracy those patients with advanced stage EOC who will respond to the standard chemotherapy [long-term survivors (>7 yrs)] and those who will not do so [short-term survivors (<3 yrs)]. Our three prognostic biomarker models were developed with 34 subjects and validated with 20 unknown (new and different) subjects. Both the overall biomarker model sensitivity and specificity ranged from 95.83% to 100.00%. The 12 most significant genes identified, which are also the input variables to the three mathematical functions, constitute three distinct gene networks with the following functions: 1) production of cytoskeletal components, 2) cell proliferation, and 3) cell energy production. The first gene network is directly associated with the mechanism of action of anti-tubulin chemotherapeutic agents, such as taxanes and epothilones. This could have a significant impact in the discovery of new, more effective pharmacological treatments that may significantly extend the survival of patients with advanced stage EOC.


Synthetic and theoretical studies of cyclobuta[1,2:3,4]dicyclopentene. Organocobalt intermediates in the construction of the unsaturated carbon skeleton and their transformation into novel cobaltacyclic complexes by C-C insertion.
Theoretical and synthetic studies of the tricyclic 10pi-electron hydrocarbon cyclobuta[1,2:3,4]dicyclopentene (1), a nominally aromatic structure that has never been synthesized, are described. Geometry optimization by density-functional-theory calculations (B3LYP/6-31G(d,p)) predict that 1 is a D(2h) symmetric structure with nonalternant C-C single and double bonds. The calculations also predict that 1 is 4.7 kcal/mol higher in energy than the isomeric hydrocarbon 1,6-didehydro[10]annulene (2), a molecule known to isomerize to 1,5-didehydronaphthalene (4) above -50 degrees C. Calculated enthalpic changes of homodesmotic reactions support the notion that 1 is an aromatic molecule with a resonance stabilization energy (RSE) about half to two-thirds that of benzene on a per-molecule basis. Investigations of potential synthetic pathways to 1 initially utilized as starting material the tricyclic carbonate 11, the product of an intramolecular [2 + 2]-photocyclization reaction. In these studies, 11 was transformed in several steps to the distannane 12, which upon treatment with boron fluoride ethyl etherate is believed to have formed the unstable hydrocarbon bicyclopentadienylidene (13). In an effort to avoid cleavage of the central, four-membered ring of unsaturated tricyclo[18.104.22.168(2,6)]decane intermediates (perhaps the result of 10-electron electrocyclic ring opening of the tetraene 8), synthetic approaches to 1 employing cobalt-cyclobutadiene complexes 18 and 19 were pursued. Treatment of 18 with excess methyllithium led to the novel cobaltacyclic product 30, and dehydration of 19 in the presence of pyridine produced the ring-opening cobaltacyclic product 35. It is proposed that both processes may occur by a 10-electron electrocyclic ring-opening reaction of eta(2)-organocobalt intermediates. These processes may be related to the hypothetical transformation of tetraene 8 to bicyclopentadienylidene (13).


The Clinical Characteristics and Prognosis of Different Age Patients with Lung Cancer.
Cancer is closely related to age, and the incidence of cancer increases with age. However, there are few studies on the relationship between age and clinical characteristics of lung cancer. We collected all the consecutive lung cancer cases from 2012 to 2017 in our hospital and divided them into 6 groups according to their ages: ≤40 y/o, 41~50 y/o, 51~60 y/o, 61~70 y/o, 71~80 y/o and >80 y/o. The clinical characteristics and prognosis of these patients were evaluated. There were 1143 cases diagnosed in our hospital from 2012 to 2017. There were more non-smokers (p<0.01), stage IV (p<0.01) and anaplastic lymphoma kinase (ALK) fusion (p<0.01) patients but less stage I patients in ≤40 y/o group compared with other age groups. It seemed that older patients were more likely had co-exist driver gene mutations (p=0.04). There was no significant difference in overall survival (OS) among these 6 age groups. However, the age may be an independent prognostic factor compared with the patients in ≤40 y/o group, the patients in >80 y/o group were associated with a higher mortality risk, while the patients in other groups had the similar mortality risk. There are some differences in clinical characteristics and prognosis among different age groups. The reasons behind the phenomenon are largely unclear. The age should be taken into account when we develop clinical trials.


[Evaluating the activity of the Italian Mental Health Services inpatient and residential facilities: the PRISM (Process Indicator System for Mental health) indicators].
This article describes the activities of a project aimed at developing a system of process and process/outcome indicators suitable to monitor over time the quality of psychiatric care of Italian inpatient and residential psychiatric facilities. This system, named PRISM (Process Indicator System for Mental health), was developed by means of a standardized evaluation made by a panel of experts and a consecutive pilot study in 17 inpatient and 13 residential psychiatric facilities. A total of 28 indicators were selected from a set of 251 candidate indicators developed by the most relevant and qualified Italian and international authorities. These indicators are derived by data from medical records and information about characteristics of facilities, and they cover processes of care, operational equipment of facilities, staff training and working, relationships with external agencies, and sentinel events. The procedure followed for the development of the indicator system was reliable and innovative. The data collected from the pilot study suggested a favourable benefit-cost ratio between the workload associated with regular use of the indicators into the context of daily clinical activities and the advantages related to the information gathered through regular use of the indicators. CONCLUSIONS.:The PRISM system provides additional information about the healthcare processes with respect to the information gathered via routine information systems, and it might prove useful for both continuous quality improvement programs and health services research.


[Changes of P-gp expression in rats' small intestine and effects on uptake of levofloxacin after acute exposure to hypoxia].
The drug transporter play a key role in the absorption of drugs. Investigation of the changes of drug transporters in response to hypoxia will provide insight into the mechanism of drug absorption. In this study we investigated the mRNA and protein expression of the transporter P-gp after acute hypoxia, and evaluated the effects of P-gp changes on absorption of levofloxacin in the intestine. The relative expression of m RNA and protein were reduced by 50.80% and 71.30%(P < 0.05). In the single-pass intestinal perfusion model, the intestinal wall permeability was increased by 56.16%, 226.00%, 77.74% and 141.00% in the time intervals at 30-60 min, 60-90 min, 90-120 min and 120-150 min although P-gp expression was decreased(P < 0.05). These results suggest that hypoxia may decrease the expression of P-gp in the intestine to reduce the excretion of levofloxacin and increase the absorption.


Compliance with home rehabilitation therapy by parents of children with disabilities in Jews and Bedouin in Israel.
Among key points in making progress and succeeding with a therapeutic programme for children with disabilities is parental compliance with the regime for their child. The purpose of this study was to evaluate factors influencing compliance with home therapy in the Jewish and Bedouin populations. Data were collected by structured questionnaires. A total of 193 families participated (84% response rate) with children who ranged in age from 6 months to 6 years (mean age at first visit to the centre was 9.5 years in Jews and 16.1 years in Bedouin). Compliance was significantly lower among the Bedouin. Multivariate regression analysis showed that the strongest contributory factor in lack of compliance was being Bedouin. The second factor was intensity of questioning destiny, indicating that parents with these feelings may be less likely to comply with therapeutic regimes. Other factors which were associated with compliance were parents' education and socioeconomic status: lower levels on these dimensions corresponded with lower parental compliance. These results were illuminated by a trial intervention programme for Bedouin families which involved telephone contact, translation facilities, and detailed explanations during visits to the centre. Intervention increased the compliance rate of the Bedouin appointments with specialists to 76% (91 of 120 appointments) thereby reaching similar levels to those of the Jewish group. These preliminary results indicate that the strong association between non-compliance and being Bedouin may be due to factors of communication, and that the Bedouin are receptive to therapeutic interventions when communicated in their own language.


A bi-stage feature selection approach for COVID-19 prediction using chest CT images.
The rapid spread of coronavirus disease has become an example of the worst disruptive disasters of the century around the globe. To fight against the spread of this virus, clinical image analysis of chest CT (computed tomography) images can play an important role for an accurate diagnostic. In the present work, a bi-modular hybrid model is proposed to detect COVID-19 from the chest CT images. In the first module, we have used a Convolutional Neural Network (CNN) architecture to extract features from the chest CT images. In the second module, we have used a bi-stage feature selection (FS) approach to find out the most relevant features for the prediction of COVID and non-COVID cases from the chest CT images. At the first stage of FS, we have applied a guided FS methodology by employing two filter methods: Mutual Information (MI) and Relief-F, for the initial screening of the features obtained from the CNN model. In the second stage, Dragonfly algorithm (DA) has been used for the further selection of most relevant features. The final feature set has been used for the classification of the COVID-19 and non-COVID chest CT images using the Support Vector Machine (SVM) classifier. The proposed model has been tested on two open-access datasets: SARS-CoV-2 CT images and COVID-CT datasets and the model shows substantial prediction rates of 98.39% and 90.0% on the said datasets respectively. The proposed model has been compared with a few past works for the prediction of COVID-19 cases. The supporting codes are uploaded in the Github link: https://github.com/Soumyajit-Saha/A-Bi-Stage-Feature-Selection-on-Covid-19-Dataset.


Comparison of intraperitoneal and intratesticular ozone therapy for the treatment of testicular ischemia-reperfusion injury in rats.
We compare the efficacy of intratesticular ozone therapy with intraperitoneal ozone therapy in an experimental rat model. For this purpose, 24 rats were divided into four groups including sham-operated, torsion/detorsion, torsion/detorsion plus intraperitoneal ozone (O-IP), and torsion/detorsion plus intratesticular ozone (O-IT). The O-IP ozone group received a 4 mg kg-1 intraperitoneal injection of ozone, and the O-IT group received the same injection epididymally. At 4 h after detorsion, the rats were sacrificed and orchiectomy materials were assessed histopathologically. Spermatogenesis in the seminiferous tubules and damage to the Sertoli cells were histopathologically evaluated in the testes using the Johnsen scoring system. i-NOS and e-NOS activities in the testis tissue were also evaluated. Torsion-detorsion caused a decreased Johnsen score and increased apoptosis of spermatogonial and Sertoli cells. Ozone injection prevented increases in Johnsen score and i-NOS level. e-NOS level of the O-IP group was significantly lower than that of the O-IP group, and i-NOS level of the O-IT group was significantly lower than that of the O-IP group. Local ozone therapy is more effective than systemic ozone therapy at improving IRI-related testicular torsion. Our study is the first to show that the efficacy of intratesticular implementation of ozone therapy is higher than that of intraperitoneal ozone therapy.


Use of N-Acetylcysteine in Amphetamine-Induced Acute Liver Failure.
Acute liver failure (ALF) is a serious complication of many drugs. Amongst recreational drugs, cocaine, amphetamines and ecstasy (methylenedioxymethamphetamine) have been known to cause ALF as a complication. However, the true effects and management on the liver of such cases have not been well reported and treatment of such conditions needs prompt action. N-acetylcysteine (NAC) is a known hepatoprotective agent but remains controversial in the use of recreational drug-induced acute liver injury. We present a case of ALF secondary to amphetamine ingestion, with a rapid recovery after administration of intravenous NAC.


Adrenal insufficiency and stage D carcinoma of the prostate.
A patient with stage D prostatic cancer but in reasonably good general health was discovered to have adrenal failure and tumor destruction of the adrenal glands. Because prostatic cancer is common and compatible with prolonged survival, we surveyed other patients with stage D prostatic cancer. On initial screening with the cosyntropin test, we found that 5 of 14 patients failed to respond with an increase in serum cortisol of 10 micrograms/dL, suggesting an adrenal failure incidence of 36%. Retesting, however, indicated that probably all of these were false-positive results.


Childhood trauma and psychotic experiences in a general population sample: A prospective study on the mediating role of emotion regulation.
The causal role of childhood trauma for psychosis is well established, but the mechanisms that link trauma to psychosis are largely unknown. Since childhood trauma is known to cause difficulties in emotion regulation (ER) and patients with psychosis show impaired ER, we hypothesize that impaired ER explains why people with a background of trauma are prone to psychotic experiences. The study used a longitudinal cohort design based on a community sample (N=562) from Germany, Indonesia, and the United States. Childhood trauma was assessed at baseline. ER and psychotic experiences (defined as positive symptom frequency and related distress) were measured repeatedly at a 4-, 8-, and 12-month follow-up. Cross-lagged panel and longitudinal mediation analyses with structural equation modeling were used to test the predictive value of ER on psychotic experiences and its mediating role in the association of childhood trauma and psychotic experiences. The cross-lagged paths from impaired ER to symptom distress (but not frequency) were significant. However, there was also evidence for the reverse causation from symptom frequency and distress to impaired ER. ER partially mediated the significant prospective paths from childhood trauma to symptom distress. The findings demonstrate that ER plays a role in translating childhood trauma into distressing psychotic experiences in later life. Moreover, the findings point to a maintenance mechanism in which difficulties in ER and symptom distress exacerbate each other. Thus, ER could be a promising target for interventions aimed at prevention of psychosis.


A new family of hetero-tri-metallic complexes [M(CuTb)]n (n = 1, 2, ∞; M = Co, Cr, Fe): synthesis, structure and tailored single-molecule magnet behavior.
A new family of hetero-tri-metallic complexes [M(CuTb)]n (M(III) = Co, Cr, Fe; n = 1, 2, ∞), composed of three series of three compounds (oligo- and poly-nuclear complexes based on [Cu-Tb] subunits), is presented and fully characterized. These nine compounds, viewed as different assemblies of single-molecule magnet (SMM) building blocks, connected to various hexacyanometalate centers, illustrate how the SMM behavior of the [CuTb] moiety can be modulated via the control of intermolecular interactions. Specifically, the combination of the "non-innocent" diamagnetic [Co(III)(CN)6](3-) center with a [Cu-Tb](3+) moiety enabled isolation of the magnetic entities, resulting in an improvement of the SMM behavior (ranging from Ueff = 5-7 cm(-1) to 15-17 cm(-1)).


Consequences of restricted feeding/refeeding cycles in lean and obese female Zucker rats.
Lean and obese female Zucker rats underwent four, 6-wk cycles of restricted feeding/refeeding. Restricted-fed, lean (RL) rats lost and then regained sufficient weight in each cycle to weigh the same amount as ad libitum-fed, lean (AL) rats at the end of each refeeding period. After the final period of restricted intake, RL rats had significantly lower parametrial and retroperitoneal pad weights and fat cell sizes than AL rats, but their organ growth and lipogenic enzymes were not affected. After the final refeeding period, there were no differences between RL and AL rats except in cumulative food intake. During the first period of restricted intake restricted-fed, obese (RO) rats did not lose weight; however, they were unable to attain the body weight of ad libitum-fed, obese (AO) rats during the subsequent refeeding period. In later cycles, RO rats lost and regained weight, but always weighed significantly less than AO rats. Following the final restricted feeding and refeeding periods, fat pad weights and cell numbers were significantly lower in RO than AO rats, but fat cell size was not affected. Liver weight and lipogenic enzymes were lower in RO than in AO rats after the final period of restricted intake, but were similar to AO rats after the final refeeding period. Permanent effects on heart and kidney growth were found in RO rats. Obese rats appeared to respond differently than lean rats to this form of dietary intervention.


Levofloxacin in the treatment of pneumonia in intensive care unit patients.
In this study, we analyzed 302 patients with pneumonia admitted to the Intensive Care Unit (ICU) who were treated with levofloxacin (LFX) either as monotherapy or combined therapy. Pneumonia was classified as community-acquired in 220 (73%) patients, extra-ICU nosocomial-acquired in 43 (14%), and intra-ICU nosocomial-acquired in 39 (13%) patients. Treatment with LFX was used empirically in 85.7% of the cases. Initial doses of LFX were 500 mg every 24 h in 48.5% of the cases and 500 mg every 12 hours in 48.3%. Treatment was maintained for a mean (SD) of 12.6 (21.9) days. Treatment began as monotherapy in 116 (38.4%) patients and as combination therapy in 186 (61.6%). The factors that influenced the choice of combined treatment were septic shock (odds ratio [OR] 3.03; 95% confidence interval [CI] 1.50-6.12) and the presence of two or more extrinsic factors (OR 1.83; 95% CI 1.04-3.23), while young age was a variable associated with monotherapy (OR 0.98; 95% CI 0.96-0.99). An etiological diagnosis was made in 61.6% of the cases. LFX administration was changed from the intravenous route to oral administration in 85 (28.6%) patients. Satisfactory clinical response (cure and improvement) was achieved in 69.4% of the community-acquired pneumonia, in 55.8% of the extra-ICU nosocomial infection, and in 78.3% of the intra-ICU nosocomial infection. The overall mortality rate was 31.5%. Variables associated with death during ICU stay were combined therapy (OR 3.07; 95% CI 1.23-7.65), septic shock (OR 3.49; 95% CI 1.30-9.39), or therapeutic failure (OR 32.6; 95% CI 13.5-78.9). A total of 15% of the patients experienced adverse effects possibly or probably related the antibiotic given.


Myofiber angle distributions in the ovine left ventricle do not conform to computationally optimized predictions.
Recent computational models of optimized left ventricular (LV) myofiber geometry that minimize the spatial variance in sarcomere length, stress, and ATP consumption have predicted that a midwall myofiber angle of 20 degrees and transmural myofiber angle gradient of 140 degrees from epicardium to endocardium is a functionally optimal LV myofiber geometry. In order to test the extent to which actual fiber angle distributions conform to this prediction, we measured local myofiber angles at an average of nine transmural depths in each of 32 sites (4 short-axis levels, 8 circumferentially distributed blocks in each level) in five normal ovine LVs. We found: (1) a mean midwall myofiber angle of -7 degrees (SD 9), but with spatial heterogeneity (averaging 0 degrees in the posterolateral and anterolateral wall near the papillary muscles, and -9 degrees in all other regions); and (2) an average transmural gradient of 93 degrees (SD 21), but with spatial heterogeneity (averaging a low of 51 degrees in the basal posterior sector and a high of 130 degrees in the mid-equatorial anterolateral sector). We conclude that midwall myofiber angles and transmural myofiber angle gradients in the ovine heart are regionally non-uniform and differ significantly from the predictions of present-day computationally optimized LV myofiber models. Myofiber geometry in the ovine heart may differ from other species, but model assumptions also underlie the discrepancy between experimental and computational results. To test the predictive capability of the current computational model would we propose using an ovine specific LV geometry and comparing the computed myofiber orientations to those we report herein.


Modified tobacco use and lifestyle change in risk-reducing beliefs about smoking.
This study examined beliefs about potential risk-reduction strategies for tobacco users among a large group of young adults. Strategies examined included switching to low-yield cigarettes, replacing cigarettes with cigars, switching from cigarettes to smokeless tobacco, adopting a healthy diet, and engaging in regular exercise. One-year longitudinal survey of 36,012 young adults (mean 20.1 years) entering the U.S. Air Force from October 1999 to September 2000. Smokers generally rated the strategies as providing more risk-reduction potential than never smokers or ex-smokers, although the group differences were small. Diet, exercise, and switching to low-yield cigarettes were rated as providing the most health benefits, regardless of smoking status. Smokers who had either changed their diet or exercise to lower their risks from smoking had significantly lower perceived personal risk of developing a tobacco-related disease than other smokers. Smokers who believed that switching to smokeless tobacco would lower the health risks associated with smoking were more likely, while smokers reporting switching to low-yield cigarettes were significant less likely, to quit during a 1-year follow-up period. Beliefs about the risk-reduction benefits of both changes in tobacco use and health behaviors may impact tobacco use attitudes and practices.


Evaluation of the immunogenicity and impact on the latent HIV-1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy-treated subjects.
Vaccines may be key components of a curative strategy for HIV-1. We investigated whether a novel immunogen, HIVconsv, designed to re-direct T cell responses to conserved viral epitopes, could impact the HIV-1 reservoir in chronic antiretroviral therapy (ART)-treated subjects when delivered by modified vaccinia virus Ankara (MVA). Nineteen virologically suppressed individuals were randomized to receive vaccinations with MVA.HIVconsv (5.5 × 107 plaque-forming units, pfu, n = 8; 2.2 × 108 pfu, n = 7) or placebo (n = 4) at 0, 4 and 12 weeks. Magnitude, breadth and antiviral function of vaccine-induced T cells, cell-associated HIV-1 DNA in circulating CD4+ T cells and residual viremia in plasma were measured before and after vaccination. 90% of subjects completed the vaccine regimen; there were no serious vaccine-related adverse events. The magnitude of HIVconsv-specific IFN-γ-secreting T cells was not significantly boosted in vaccinees when compared with placebos in ex vivo Elispot assays, due to greater than expected variation in HIV-specific T cell responses in the latter during the observation period. Ex vivo CD8+ T cell viral inhibitory capacity was modest but significantly increased post-vaccination with MVA.HIVconsv at the higher dose (p = 0.004) and was positively correlated with the frequency of HIVconsv-specific CD8+ CD107+ IFN-α± T cells (r = 0.57, p = 0.01). Total HIV-1 DNA and residual viral load did not change significantly from baseline in any group. Homologous prime-boost vaccination with MVA.HIVconsv was safe in HIV-positive ART-treated subjects but showed modest immunogenicity and did not significantly change the size of the viral reservoir. MVA.HIVconsv may be more effective when used in a heterologous prime-boost vaccination regimen and when combined with a latency-reversing agent. NCT01024842.


Genetics, behaviour and psychiatry: historical burdens and perspective.
Familiar, twin, adoption and linkage studies represent the usual tools for assessing the possible role of genetics in mental disease. These genetic approaches have been refined in the last years and a number of methodological problems are absent in recent approaches. While there is no doubt that schizophrenia, mood disorders and autism are characterized by a genetic component no linkage study has been successful up to date, apart, probably, the case of autism. The existence of a genetic component does not minimize the role of the environment and of critical life events. It is also evident that no major genes are responsible for these psychiatric diseases: thus, quantitative trait loci analyses might prove fruitful in future research to track the role of different genes contributing to the outcome of different psychopathologies. The main problem, however, is the difficulty of carrying out quantitative analyses since the today's diagnostic tools do not allow a quantitative approach to these phenotypes.


Is Atrial Fibrillation a Stroke Risk Factor or Risk Marker? An Appraisal Using the Bradford Hill Framework for Causality.
Atrial fibrillation (AF) is strongly associated with stroke risk but association on its own does not necessarily imply causality. Is AF a cause (risk factor) of stroke? Would treatment that reduces AF burden also reduce the burden of stroke? Or, perhaps, AF is a risk marker associated with a vascular syndrome in which there is co-existing atrial structural and electrical remodelling that results in the clinical manifestation of AF and the risk of stroke in parallel. A number of recent studies appear to detach AF as a direct cause of stroke. Studies in which cardiac implantable devices have been used to collect AF data preceding stroke appear to show no immediate temporal relationship. The Global Anticoagulant Registry in the Field - Atrial Fibrillation (GARFIELD-AF) a large worldwide registry of non-valvular AF, has shown that the risk of death exceeds the risk of stroke and that mortality, together with stroke and bleeding risk, is predicted by other vascular risk factors, defined by the CHA2DS2VASc score. Sir Bradford Hill proposed criteria to assess whether two associated factors are causal, more than 50 years ago. This method of analysing cause and effect in a complex scenario could be applied to AF and stroke. This paper aims to clinically appraise the evidence for each criterion outlined by Bradford Hill to single out whether the collective data supports one or the other.


Experience from the use of absorbable type I collagen as haemostatic agent in obstetric and gynecological operations.
During the third stage of labour there are a lot of causes of significant hemorrhage. The commonest causes of acute hemorrhage are the uterine atony, the retained placenta, the lower tract lacerations, uterine rupture, placenta accreta, hereditary coagulopathy. Also, there could be significant bleeding, during caesarian section, usually at the time of removal of the placenta in cases of low lying placenta or placenta previa. A lot of times we have to confront serious hemorrhages in gynecological procedures like hysterectomies in cases of cervical, uterine or ovarian cancers. In order to deal with these problems successfully, general and specific measures are being taken. In cases of atonic uterus when all the other methods are unsuccessful we have to proceed to ligation of the internal iliac artery or even hysterectomy. We have tried to use the hemostatic type I collagen in obstetrical and gynecological cases in order to control the bleeding. We have used the collagen type I totally in 8 cases. Five of them were cases of atonic uterus after normal delivery or caesarian section and three of them were gynecological cases of uterine fibroids and ovarian cancer. By placing the collagen type I over the bleeding surfaces we have realized that in a very short period of time, there has been satisfactory control of the bleeding and immediate clinical improvement of the patient. In four out of five obstetrical cases that we have used the type I collagen, we have managed to avoid the hysterectomy.


Molecular genomic characterization of tick- and human-derived severe fever with thrombocytopenia syndrome virus isolates from South Korea.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral disease caused by the SFTS virus (SFTSV) from Bunyaviridae that is endemic in East Asia. However, the genetic and evolutionary characteristics shared between tick- and human-derived Korean SFTSV strains are still limited. In this study we identify, for the first time, the genome sequence of a tick (Haemaphysalis longicornis)-derived Korean SFTSV strain (designated as KAGWT) and compare this virus with recent human SFTSV isolates to identify the genetic variations and relationships among SFTSV strains. The genome of the KAGWT strain is consistent with the described genome of other members of the genus Phlebovirus with 6,368 nucleotides (nt), 3,378 nt, and 1,746 nt in the Large (L), Medium (M) and Small (S) segments, respectively. Compared with other completely sequenced human-derived Korean SFTSV strains, the KAGWT strain had highest sequence identities at the nucleotide and deduced amino acid level in each segment with the KAGWH3 strain which was isolated from SFTS patient within the same region, although there is one unique amino acid substitution in the Gn protein (A66S). Phylogenetic analyses of complete genome sequences revealed that at least four different genotypes of SFTSV are co-circulating in South Korea, and that the tick- and human-derived Korean SFTSV strains (genotype B) are closely related to one another. Although we could not detect reassortant, which are commonly observed in segmented viruses, further large-scale surveillance and detailed genomic analysis studies are needed to better understand the molecular epidemiology, genetic diversity, and evolution of SFTSV. Full-length sequence analysis revealed a clear association between the genetic origins of tick- and human-derived SFTSV strains. While the most prevalent Korean SFTSV is genotype B, at least four different genotypes of SFTSV strains are co-circulating in South Korea. These findings provide information regarding the molecular epidemiology, genetic diversity, and evolution of SFTSV in East Asia.


Hartmann's procedure vs. abdominoperineal resection for palliation of advanced low rectal cancer.
In managing advanced low rectal adenocarcinomas in medically fit patients, surgical resection offers the best palliation. Tenesmus, bleeding per rectum, sacral pain, and sciatic pain are common complaints, which are not relieved by radiotherapy or fulguration. The most appropriate resection, however, remains controversial. Abdominoperineal resection is faster and simpler to perform but leaves behind a perineal wound with associated complications. Hartmann's procedure requires adequate mobilization below the tumor and may be technically more demanding but avoids a perineal wound. Therefore, an analysis of outcome in patients treated by Hartmann's procedure vs. abdominoperineal resection was made. Fifty-four symptomatic patients with advanced rectal adenocarcinoma arising within a median of 5 (range, 4-8) cm from the anal verge treated between June 1989 and October 1995 were studied. Twenty-eight patients (17 males; mean age, 67.6 +/- 10.3 years) had Hartmann's procedure, and 26 patients (12 females; mean age, 68.8 +/- 8.3 years) were treated by abdominoperineal resection. Mean follow-up was 23.5 months (+/-17.5) and 18.6 months (+/-12.9) in Hartmann's procedure and abdominoperineal groups, respectively. Mean operative time was 138.4 +/- 26.7 minutes for Hartmann's procedure group and 124.6 +/- 27.1 minutes for the abdominoperineal resection group (P > 0.05; not significant). Postoperatively, Hartmann's procedure group started oral intake at a mean of 2.3 days, and stomas were functioning at a mean of 3.1 days compared with 2.6 days for oral intake and 3 days for stoma functioning in the abdominoperineal resection group. Hartmann's procedure group was ambulant after a mean of 2.4 days vs. a mean of 3.2 days in the abdominoperineal resection group. Postoperative abdominal wound infection occurred in 18 and 19 percent, respectively, in Hartmann's procedure and abdominoperineal resection groups. Forty-six percent of patients had perineal wound sepsis, and 38 percent had perineal wound pain in the abdominoperineal resection group. These complications were absent in Hartmann's procedure group. Postoperative stay was similar in both groups. We conclude that Hartmann's procedure offers superior palliation compared with abdominoperineal resection because it provides good symptomatic control without any perineal wound complications and pain.


A methodological improvement and system validation to obtain precise behavioral parameters for schedule-induced polydipsia.
A Schedule-Induced Polydipsia (SIP) animal behaviors monitor system was devised. The system included a software package to acquire data and to format the data storage of the animal behavior in the experiment was designed. Data analysis software will also extract the necessary information from recorded data. The SIP experimental apparatus consists of a number of subsystems. They are operant chambers, event counters, signal acquisition and storage system. The operant chamber is equipped with hopper, pellet and lick sensor and locomotion detector. The data acquisition and storage subsystem are custom designed that run on IBM-PC. The discrete time markers for pellet drop, bar pressing and licking water were recorded at 200 Hz. The image of rat locomotion was recorded at 10 Hz. A test of four different stages of animal to verify the accuracy of the system was reported in this article. The food-deprived rats that were exposed to the intermittent food schedule (1 per minute) exhibit an excess drinking behavior. The animal behaviors that were monitored during the scheduled events are adjunctive, facultative and terminal behavior. The volume of water intake was also recorded for reference. The real time data is stored chronologically into two types of data file. Therefore, a special data analysis procedure is designed to extract the results for off-line statistic analysis. The extracted parameters for animal behaviors analyzing including drinking efficiency, inter-lick intervals, number of drinking bursts, size of burst, temporal distribution of licking, temporal distribution of bar pressing and locomotion. The system can be employed in many different SIP studies such as investigating the effect of acute and chronic influence of amphetamine.


On the importance of congruence between psychiatric staff and patient about the patient's status.
This study explores the usefulness of a method for comparing the congruence of the staff's and the patients' perceptions of the patients' well-being. At a psychiatric rehabilitation clinic, a comparison was made between the patients' and the staff's views of the patients' well-being. The staff and the patients completed questionnaires about the patients' well-being on ten occasions during a 5-year period. Through a principal components analysis of the questionnaire scores, two conceptually similar dimensions (health-illness, and contact-distance) were identified on each set of scores. The staff and patient ratings on the two dimensions could thus be compared. During the time of the study, a reorganisation of the clinic was made. This made it possible to compare older and newer units. The results indicated that the staff at long-existing units rated the patients' health as lower than the patients did, whereas the staff at newer units rated the patients' health as better than the patients did. The staff at units where the patients lived in their own apartments saw the patients as less contact-seeking than the patients did, and the staff at in-patient units saw the patients as more contact-seeking than the patients did. The two-dimensional PC-models made it possible to visually illustrate the developments for three individual patients. The results thus showed that the method is useful for research purposes as well as for clinical evaluations. In the final section, problems and assets of the method are discussed.


Minimally invasive therapies for Peyronie's disease: the current state of the art.
Peyronie's disease (PD) is a relatively common condition that can result in significant penile deformity, sexual dysfunction, and psychological bother. Surgical straightening offers the highest probability of success during the stable phase of the disease. However, for men in the acute phase of PD or for those with less severe deformity who elect to avoid surgery, a variety of non-surgical treatment options are available. Oral therapies, including L-citrulline and pentoxifylline, are most useful as part of a combination regimen rather than as monotherapy. Intralesional therapy with IFN-α2b, verapamil, and collagenase clostridium histolyticum (CCH) can cause significant reduction in penile curvature, yet these results may not be clinically significant for men with more severe curvature. Further investigation into the timing of administration and optimal patient characteristics is required. Penile traction therapy offers a clinically significant improvement in penile length and curvature. However, this has traditionally required hours of daily therapy. Overall, a combination of oral, topical, injection and traction therapies may provide the most significant benefit among the non-surgical modalities for PD.


Failure mode transformation of ZnO nanowires under uniaxial compression: from phase transition to buckling.
The failure modes of ZnO nanowires (NWs) with hexagonal cross section subjected to a uniaxial load are systematically investigated by using molecular dynamics (MD) simulations and two theoretical models considering the surface effect. Our results show that two different failure modes of the phase transition and buckling are triggered when the NWs are under uniaxial compression along the [0001] direction, in which the transformation between the two modes is related to the slenderness ratios of the NWs. Such slenderness-ratio-dependent mode transformation is mainly attributed to the competition between the critical stresses of phase transition and buckling. The Euler and Timoshenko models considering surface effect are further proposed to derive the critical slenderness for such mode transformation. The obtained analytical threshold values agree well with those of present MD simulations. Our results should be of great help for shedding some light on the design and application of functional devices based on ZnO NWs.


Extent of ischaemia caused by hepatic vascular exclusion as evaluated in a canine model.
1. The difference in the extent of liver ischaemia between a hepatic vascular exclusion model and an inflow occlusion model were investigated by determining Indocyanine Green retention and hepatic mitochondrial redox state during 2 h of ischaemia in 10 mongrel dogs. The splanchnic venous bed and/or the infra-hepatic inferior vena cava were decompressed by pump-driven veno-venous bypass. 2. The Indocyanine Green retention test revealed that there was no hepatic blood flow in the hepatic vascular exclusion model during ischaemia (96.8 +/- 0.73% retention of the dye after 20 min), whereas hepatic blood perfusion was still present significantly in the inflow occlusion model (78.1 +/- 1.19% retention of the dye after 20 min) (P less than 0.01). 3. The mitochondrial redox potential of the liver in the dogs with hepatic vascular exclusion decreased immediately after the induction of ischaemia and remained fixed at extremely low levels. By contrast, in the dogs with inflow occlusion the redox potential decreased gradually after induction and was maintained significantly higher than that in dogs with hepatic vascular exclusion during 2 h of ischaemia (P less than 0.01). 4. It is concluded that the extent of liver ischaemia in the hepatic vascular exclusion model with pump-driven shunt is significantly different from that in the inflow occlusion model with shunt.


BCG vaccine modulates intestinal and systemic response to beta-lactoglobulin.
Beta-Lactoglobulin (BLG) is a clinically important antigen in cow's milk and one of the major allergens causing cow's milk allergy. Bacillus Calmette-Guerin (BCG) vaccination has been suggested to modify immune response possibly decreasing the risk of allergy to some antigens in both human and experimental animals. In the present study, we have analyzed whether the early BCG vaccination has any effect on the markers of systemic and gastrointestinal (GI) sensitization to BLG. We immunized two groups of Hooded-Lister rat puppets with intraperitoneal injections of native BLG at 43 and 62 days with pertussis vaccine as adjuvant, one group receiving additionally BCG. The animals were then fed native and denatured milk products twice weekly from 73 to 131 days of age, when they were killed. Control group was not vaccinated and received normal rat forage. Total immunoglobulin E (IgE) levels and BLG-specific IgG(1) and IgG(2a) concentrations were determined in serum samples. Spontaneous interleukin (IL)-4 and interferon (IFN)-gamma production from duodenal specimens were measured, and the inflammatory cells were quantitated in specimens from different sections of the GI tract. Administration of BCG simultaneously with BLG resulted in reduced IgE concentration in serum, while the specific IgG(1) and IgG(2a) antibody responses and the spontaneous secretion of IL-4 and IFN-gamma were not affected. Furthermore, BCG-induced eosinophilic infiltration and increase of intraepithelial lymphocytes (IEL) in the GI mucosa, and a trend toward increased number of lamina propria mononuclear inflammatory cells in the colon (BCG compared with BLG, p = 0.09; BCG compared with controls, p = 0.02). Controls showed increment of IgG(1) response in comparison with the BLG group (p = 0.04) and increase of mucosal eosinophilic infiltration. The BCG modified the response to BLG both at the systemic level as shown by decrease of total IgE and at GI mucosa where increase of eosinophilic infiltration and increased number of IEL were seen. Increment of IgG(1) level and eosinophils in the controls might be related with the lack of modulatory effect of pertussis vaccination. A shift of response toward the lower GI tract after BCG immunization as shown by a trend for increase of mononuclear inflammatory cells in colon lamina propria mimics disease development in some cases of clinical food allergy, and emphasizes the need for evaluation of the changes in the whole GI tract in food allergy models.


Cannabis sativa: effects on brain function and ultrastructure in rhesus monkeys.
Two studies, designed to control for as many variables as possible, were conducted in 21 rhesus monkeys, some with brain electrodes and some unoperated, to determine the effects of marijuana on brain function and ultrastructure. Some monkeys were exposed to smoke of active marijuana (using different dose schedules), some were administered delta-9-THC (0.69 mg/kg iv), and others were exposed to smoke of inactive marijuana (from which all cannabinols had been removed). To deliver smoke to the monkeys, two different apparatuses were used. Dose schedules comparable to those of human marijuana smokers were established, as determined by plasma levels of delta-9-THC. After 2- to 3-months' exposure, the monkeys that were heavy- and moderate-smokers of active marijuana, and those administered delta-9-THC iv, developed chronic recording changes at deep brain sites, most marked in the septal region, hippocampus, and amygdala. These changes persisted throughout the exposure period (6 or 8 months) and during the postexposure observation period (1 to 8 months). Brains of these electrode-implanted monkeys, as well as those without electrodes that were exposed to delta-9-THC, showed ultrastructural alterations characterized by changes at the synapse, destruction of rough endoplasmic reticulum, and development of nuclear inclusion bodies. In contrast, brains of monkeys exposed to smoke of inactive marijuana and of unexposed controls showed no ultrastructural changes. The findings indicate that exposure to delta-9-THC, the psychoactive ingredient of marijuana, at doses commensurate with those used by human marijuana smokers can produce permanent alterations in brain function and structure of monkeys.


Ornithine decarboxylase activity is a marker of premalignancy in longstanding Helicobacter pylori infection.
Longstanding Helicobacter pylori infection may increase the risk of developing gastric adenocarcinoma. The sequence of chronic active gastritis leading to gastritis with atrophy and subsequent intestinal metaplasia is thought to be a key step in gastric carcinogenesis. Ornithine decarboxylase (ODC) activity is increased in some pre-malignant gastrointestinal conditions and is essential for malignant transformation in vitro. To measure ODC activity in the antrum of H pylori infected and non-infected subjects and to relate this to histological abnormalities associated with recent and longstanding H pylori infection. Six antral mucosal biopsy specimens were obtained from 75 patients for detailed histological assessment and measurement of ODC activity. Samples were measured in duplicate and results expressed as median, interquartile range in pmol/mg protein/h. ODC activity was significantly higher in H pylori positive (164, 88-259 pmol/mg/h) than H pylori negative subjects (99.8, 55-158 pmol/mg/h, p = 0.003). However the presence of gastritis, irrespective of the severity of inflammation or activity had no influence on ODC activity. Gastritis with atrophy was associated with increased ODC activity, which was closely related to the severity of the atrophy (p = 0.01). Similarly, ODC activity was significantly increased in subjects with intestinal metaplasia (196, 83-25) compared with those without intestinal metaplasia (111.7, 65-175, p < 0.04). These results indicate that the histological changes associated with longstanding H pylori infection rather than inflammation alone are associated with increased polyamine biosynthetic activity. This may be relevant to H pylori associated gastric carcinogenesis.


Experience with needle biopsy for coccidioidal lung nodules.
Three hundred forty-eight patients with solitary pulmonary nodules underwent needle biopsy of the lung in an endemic area for coccidioidomycosis. The purposes of the study were to establish the value of smears and cultures from needle biopsy specimens in the diagnosis of solitary coccidioidal granuloma and to determine how the final diagnosis was established for patients without a clear-cut diagnosis after initial biopsy. Spherules of Coccidioides immitis were initially identified in 49 of the 96 patients with coccidioidomas. Only three of 35 cultures from biopsy-proved coccidioidal lesions were positive (8.6% yield); nevertheless, cultures were cost-effective in nondiagnostic cases. Thoracotomy should be delayed until the results of cultures are known if findings of skin tests, serologic studies, and roentgenography make a benign diagnosis plausible.


Results of the Predictors of Response to CRT (PROSPECT) trial.
Data from single-center studies suggest that echocardiographic parameters of mechanical dyssynchrony may improve patient selection for cardiac resynchronization therapy (CRT). In a prospective, multicenter setting, the Predictors of Response to CRT (PROSPECT) study tested the performance of these parameters to predict CRT response. Fifty-three centers in Europe, Hong Kong, and the United States enrolled 498 patients with standard CRT indications (New York Heart Association class III or IV heart failure, left ventricular ejection fraction < or = 35%, QRS > or = 130 ms, stable medical regimen). Twelve echocardiographic parameters of dyssynchrony, based on both conventional and tissue Doppler-based methods, were evaluated after site training in acquisition methods and blinded core laboratory analysis. Indicators of positive CRT response were improved clinical composite score and > or = 15% reduction in left ventricular end-systolic volume at 6 months. Clinical composite score was improved in 69% of 426 patients, whereas left ventricular end-systolic volume decreased > or = 15% in 56% of 286 patients with paired data. The ability of the 12 echocardiographic parameters to predict clinical composite score response varied widely, with sensitivity ranging from 6% to 74% and specificity ranging from 35% to 91%; for predicting left ventricular end-systolic volume response, sensitivity ranged from 9% to 77% and specificity from 31% to 93%. For all the parameters, the area under the receiver-operating characteristics curve for positive clinical or volume response to CRT was < or = 0.62. There was large variability in the analysis of the dyssynchrony parameters. Given the modest sensitivity and specificity in this multicenter setting despite training and central analysis, no single echocardiographic measure of dyssynchrony may be recommended to improve patient selection for CRT beyond current guidelines. Efforts aimed at reducing variability arising from technical and interpretative factors may improve the predictive power of these echocardiographic parameters in a broad clinical setting.


Ca2+-mediated activation of phosphofructokinase in perfused rat heart.
Perfusion of the isolated rat heart with Ca2+ concentrations exceeding 3 mM activated phosphofructokinase and phosphorylase, and decreased the concentration of cyclic AMP. Half-maximal activation of phosphofructokinase occurred at 5 mM-CaCl2; significant activation of phosphorylase did not occur until the concentration of CaCl2 exceeded 12 mM. The time course for the activation of phosphofructokinase at 12 mM-CaCl2 indicated that maximal activation occurred within 2 min; when the perfusion-medium Ca2+ concentration was re-adjusted to 3 mM, the phosphofructokinase activity returned to pre-activation values within 30 s. The addition of Ca2+ to extracts of heart did not activate phosphofructokinase. The activation of phosphofructokinase by sub-maximal doses of adrenaline and Ca2+ were not additive. The activation of phosphofructokinase by 1 microM-adrenaline + 10 microM-propranolol and by 1 microM-isoprenaline was inhibited by high concentrations of K+ (22-56 mM). The activation of phosphofructokinase by 1 microM-adrenaline + 10 microM-propranolol, 12 mM-CaCl2 and by 1 microM-isoprenaline was blocked by the slow Ca2+-channel blocker nifedipine. These findings suggest that both the beta- and alpha-adrenergic mechanisms for the activation of rat heart phosphofructokinase involve an increase in the myoplasmic Ca2+ concentration. This increase may result from an inhibition of Ca2+ efflux or a stimulation of Ca2+ influx.


Increased seroreactivity to human T cell lymphoma/leukemia virus-related endogenous sequence-1 Gag peptides in patients with human T cell lymphoma/leukemia virus myelopathy.
Previously, we had shown that although only 8% of patients with large granular lymphocytic leukemia (LGLL) were infected with human T cell lymphoma/leukemia virus (HTLV)-2, almost half had antibodies to HTLV Gag and Env peptides. Herein, we investigated whether this could be due to cross-reactive antibodies to two homologous peptides in the Gag protein of the endogenous retrovirus HTLV-related endogenous sequence-1 (HRES-1). In addition, we had previously shown that patients with HTLV neurodegenerative diseases had increased seroreactivity to homologous HERV-K10 endogenous retrovirus peptides. Hence, in this study we also examined whether these patients had increased seroreactivity to the aforementioned HRES-1 Gag peptides. Sera from 100 volunteer blood donors (VBD), 53 patients with LGLL, 74 subjects with HTLV-1 or 2 infection (58 nonmyelopathy and 16 myelopathy), and 83 patients with multiple sclerosis (MS) were evaluated. The HTLV-positive myelopathy (HAM) patients had a statistically increased prevalence of antibodies to both HRES-1 Gag peptides (81%) vs. the VBD (0%), LGLL patients (13%), and MS patients (1%), and the HTLV-positive nonmyelopathy subjects (21%). The data suggest that cross-reactivity to HRES-1 peptides could be involved in the pathogenesis of HAM. The difference between the VBD and LGLL patients was also statistically significant, also suggesting a possible association in a minority of patients.


On the relationship between regional circulation and systemic blood pressure.
The relationship between regional circulation (blood flow or calculated resistance) and systemic blood pressure (BP) is only poorly documented in the range of intermediate to low BP. In 75 subjects covering the BP range from low, over intermediate, to high BP, venous occlusion plethysmographic recordings were performed at the calf and finger vessels. Correlations were calculated between regional blood flow or vascular resistance and BP defined from office and from 24 h ambulatory BP registrations, at rest and during reactive hyperaemia. At any BP level, finger blood flow at rest and during reactive hyperemia was higher than calf blood flow, and resistance was lower. The interval of 90-100 mmHg office diastolic BP was characterized by significantly (p < 0.001) higher resting finger blood flow; the increase in resting muscle blood flow was less pronounced. At rest and during reactive hyperaemia there was a stepwise increase in calf regional vascular resistance in parallel with increasing BP. For the finger circulation, increased vascular resistance was only observed for the higher BP values. Correlations between calf and finger vascular resistances and BP were positive and highly significant over the whole BP range, both for office (0.650 < r < 0.776) and for ambulatory BP (0.531 < r < 0.781). These correlations remained significant after adjustment for the age dependency. Increases in calf and finger blood flow induced by arterial occlusion were highest for the lowest BP quintiles. Our data further indicated that the capacity to dilate decreased progressively with increasing BP level (from asymptomatic low to high BP) for both calf and finger circulation.


Heparin and dermatan sulphate induced capacitation of frozen-thawed bull spermatozoa measured by merocyanine-540.
Glycosaminoglycans (GAGs) are present in the oviduct in which the major part of sperm capacitation occurs. In this study we have tested how capacitation of frozen-thawed bull spermatozoa is effected by exposure to different GAGs detectable or possibly present in oviductal fluid; i.e. heparin, hyaluronan, heparan sulphate, dermatan sulphate and chondroitin sulphate. Following exposure of different duration, the spermatozoa were stained with either Chlortetracycline (CTC) or merocyanine-540 and evaluated with epifluorescent light microscopy or flow cytometry, respectively. Heparin elicited a significant increase in the number of alive, capacitated spermatozoa, either expressed as higher merocyanine-540 fluorescence (p < 0.0001) or as B-pattern (p = 0.0021) in the CTC assay, during 4 h of incubation. When comparing the different GAG treatments one by one to the negative control in the flow cytometric study, only heparin and dermatan sulphate were significant (p < 0.0001) higher than the control at 0-30 min of incubation. Duration of incubation did not affect the proportion of capacitated spermatozoa when measured as merocyanine-540 fluorescence or CTC B-pattern, but the length of the incubation did affect the number of dead (Yo-PRO 1 positive) spermatozoa (p < 0.0001). Exposure to zona pellucida proteins significantly increased the proportion of acrosome reacted spermatozoa (p = 0.016). Both heparin and dermatan sulphate induce capacitation of frozen-thawed bull spermatozoa in vitro.


COVID-19 cases, hospitalizations and deaths in Belgian nursing homes: results of a surveillance conducted between April and December 2020.
In Belgium, the first COVID-19 death was reported on 10 March 2020. Nursing home (NH) residents are particularly vulnerable for COVID-19, making it essential to follow-up the spread of COVID-19 in this setting. This manuscript describes the methodology of surveillance and epidemiology of COVID-19 cases, hospitalizations and deaths in Belgian NHs. A COVID-19 surveillance in all Belgian NHs (n = 1542) was set up by the regional health authorities and Sciensano. Aggregated data on possible/confirmed COVID-19 cases and hospitalizations and case-based data on deaths were reported by NHs at least once a week. The study period covered April-December 2020. Weekly incidence/prevalence data were calculated per 1000 residents or staff members. This surveillance has been launched within 14 days after the first COVID-19 death in Belgium. Automatic data cleaning was installed using different validation rules. More than 99% of NHs participated at least once, with a median weekly participation rate of 95%. The cumulative incidence of possible/confirmed COVID-19 cases among residents was 206/1000 in the first wave and 367/1000 in the second wave. Most NHs (82%) reported cases in both waves and 74% registered ≥10 possible/confirmed cases among residents at one point in time. In 51% of NHs, at least 10% of staff was absent due to COVID-19 at one point. Between 11 March 2020 and 3 January 2021, 11,329 COVID-19 deaths among NH residents were reported, comprising 57% of all COVID-19 deaths in Belgium in that period. This surveillance was crucial in mapping COVID-19 in this vulnerable setting and guiding public health interventions, despite limitations of aggregated data and necessary changes in protocol over time. Belgian NHs were severely hit by COVID-19 with many fatal cases. The measure of not allowing visitors, implemented in the beginning of the pandemic, could not avoid the spread of SARS-CoV-2 in the NHs during the first wave. The virus was probably often introduced by staff. Once the virus was introduced, it was difficult to prevent healthcare-associated outbreaks. Although, in contrast to the first wave, personal protective equipment was available in the second wave, again a high number of cases were reported.


Nasal continuous positive airways pressure immediately after extubation for preventing morbidity in preterm infants.
Preterm infants being extubated following a period of intermittent positive pressure ventilation via an endotracheal tube are at risk of developing respiratory failure as a result of apnea, respiratory acidosis and hypoxia. Nasal continuous positive airway pressure appears to stabilise the upper airway, improve lung function and reduce apnea and may therefore have a role in facilitating extubation in this population. In preterm infants having their endotracheal tube removed following a period of intermittent positive pressure ventilation (IPPV), does management with nasal continuous positive airways pressure (NCPAP) lead to an increased proportion remaining free of additional ventilatory support, compared to extubation directly to headbox oxygen? Searches were made of the Oxford Database of Perinatal Trials, Medline, previous reviews including cross references, abstracts of conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language and expert informant searches in the Japanese language by Prof. Ogawa. All trials utilising random or quasi-random patient allocation, in which NCPAP (delivered by any method) was compared with headbox oxygen for post-extubation care were included. Methodological quality was assessed independently by the two authors. Data were extracted independently by the two authors. Prespecified subgroup analysis to determine the impact of different levels of NCPAP, differences in duration of IPPV and use of aminophylline were also performed using the same package. Data were analysed using relative risk (RR), risk difference (RD) and number needed to treat (NNT). Nasal CPAP, when applied to preterm infants being extubated following IPPV, reduces the incidence of adverse clinical events (apnea, respiratory acidosis and increased oxygen requirements) indicating the need for additional ventilatory support [RR 0.62 (0.49, 0.79), RD -0.175 (-0. 256,-0.095), NNT 6 (4,11)]. A trend towards reduction in the incidence of chronic lung disease at 28 days of age is also seen in the group extubated to NCPAP. This does not reach statistical significance [RR 0.86 (0.67,1.10), RD -0.069 (-0.177,0.039)]. nasal CPAP is effective in preventing failure of extubation in preterm infants following a period of endotracheal intubation and IPPV. Implication for research: further definition of the gestational age and weight groups in whom these results apply is required. Optimal levels of NCPAP as well as methods of administration remain to be determined.


Registration using tomographic projection files.
An algorithm has been developed and experimentally verified for tomographic registration--a patient positioning method using internal anatomy and standard external fiducial marks. This algorithm improves patient set-up and verification to an accuracy sufficient for tomotherapy. By implementation of this technique, the time-consuming reconstruction process is avoided. Instead, offsets in the x, y and z directions are determined directly from sinogram data by an algorithm that utilizes cross-correlations and Fourier transforms. To verify the efficiency and stability of the algorithm, data were collected on the University of Wisconsin's dedicated tomotherapy research workbench. The experiment indicates offset statistical errors of less than +/-0.8 mm for offsets up to 30 mm. With standard clinical techniques, initial patient offsets are expected to be less than 5 mm, so the 30 mm limitation is of no consequence. The angular resolution for the direction of patient translation is within the +/-2 degrees needed for tomotherapy.


Glycomimetic affinity-enrichment proteomics identifies partners for a clinically-utilized iminosugar.
Widescale evaluation of interacting partners for carbohydrates is an underexploited area. Probing of the 'glyco-interactome' has particular relevance given the lack of direct genetic control of glycoconjugate biosynthesis. Here we design, create and utilize a natural product-derived glycomimetic iminosugar probe in a Glycomimetic Affinity-enrichment Proteomics (glyco-AeP) strategy to elucidate key interactions directly from mammalian tissue. The binding partners discovered here and the associated genomic analysis implicate a subset of chaperone and junctional proteins as important in male fertility. Such repurposing of existing therapeutics thus creates direct routes to probing in vivo function. The success of this strategy suggests a general approach to discovering 'carbohydrate-active' partners in biology.


Downregulation of the inflammatory network in senescent fibroblasts and aging tissues of the long-lived and cancer-resistant subterranean wild rodent, Spalax.
The blind mole rat (Spalax) is a wild, long-lived rodent that has evolved mechanisms to tolerate hypoxia and resist cancer. Previously, we demonstrated high DNA repair capacity and low DNA damage in Spalax fibroblasts following genotoxic stress compared with rats. Since the acquisition of senescence-associated secretory phenotype (SASP) is a consequence of persistent DNA damage, we investigated whether cellular senescence in Spalax is accompanied by an inflammatory response. Spalax fibroblasts undergo replicative senescence (RS) and etoposide-induced senescence (EIS), evidenced by an increased activity of senescence-associated beta-galactosidase (SA-β-Gal), growth arrest, and overexpression of p21, p16, and p53 mRNAs. Yet, unlike mouse and human fibroblasts, RS and EIS Spalax cells showed undetectable or decreased expression of the well-known SASP factors: interleukin-6 (IL6), IL8, IL1α, growth-related oncogene alpha (GROα), SerpinB2, and intercellular adhesion molecule (ICAM-1). Apparently, due to the efficient DNA repair in Spalax, senescent cells did not accumulate the DNA damage necessary for SASP activation. Conversely, Spalax can maintain DNA integrity during replicative or moderate genotoxic stress and limit pro-inflammatory secretion. However, exposure to the conditioned medium of breast cancer cells MDA-MB-231 resulted in an increase in DNA damage, activation of the nuclear factor κB (NF-κB) through nuclear translocation, and expression of inflammatory mediators in RS Spalax cells. Evaluation of SASP in aging Spalax brain and intestine confirmed downregulation of inflammatory-related genes. These findings suggest a natural mechanism for alleviating the inflammatory response during cellular senescence and aging in Spalax, which can prevent age-related chronic inflammation supporting healthy aging and longevity.


Increased Substance Use and Poorer Mental Health in Adolescents With Problematic Musculoskeletal Pain.
Study Design Cross-sectional study. Background Adolescents with musculoskeletal pain are thought to be at greater risk of modifiable health risk behaviors, but little is known about these behaviors in adolescents with problematic pain. Objective To describe the prevalence of substance use (tobacco smoking, alcohol consumption, and illicit drugs) and poor mental health in adolescents with problematic musculoskeletal pain, compared to those without such pain. Methods Data on self-reported pain, substance use, and poor mental health were collected from 1831 year 9 students (age range, 14-16 years). Participants were considered to have problematic pain if they reported experiencing pain at least monthly over a 6-month period that also required medication or impacted 1 or more of the following: school or work, daily activities, and leisure or sporting activities. Results Almost half (46%) of the participants experienced problematic pain. Adolescents with problematic pain, compared to those without pain, reported higher substance use and poorer mental health: tobacco smoking in the last 4 weeks, 12% versus 7% (odds ratio [OR] = 1.76; 95% confidence interval [CI]: 1.25, 2.28); alcohol consumption in the last 4 weeks, 30% versus 20% (OR = 1.68; 95% CI: 1.34, 2.11); illicit drug use, 13% versus 6% (OR = 2.18; 95% CI: 1.55, 3.07); lower Mental Health Inventory scores (β = -11.43; standard error [SE], 0.96; P<.05), indicating poorer mental health; and higher Strengths and Difficulties Questionnaire total scores (β = 3.67; SE, 0.29; P<.05), indicating greater difficulties. Conclusion Adolescents with problematic pain report higher smoking, alcohol use, and use of illicit drugs and poorer mental health than adolescents without problematic pain. The experience of problematic pain could be an important consideration for substance use and chronic disease prevention. This trial is registered with the Australian New Zealand Clinical Trials Registry (reference number ACTRN12611000606987). J Orthop Sports Phys Ther 2017;47(10):705-711. doi:10.2519/jospt.2017.7441.


Quantum DFT studies on the drug delivery of favipiravir using pristine and functionalized chitosan nanoparticles.
Considering the spread of the COVID-19 pandemic, finding new drugs along with the development of effective drug delivery methods can help in the treatment of this disease. For this reason, in this research work, the possibility of drug-delivery of Favipiravir (FP), one of the drugs approved in the treatment of COVID-19, by pristine chitosan (Chit) nanoparticles (NP), and functionalized chitosan nanoparticles with N-acylate, N-methyl, O-acetyl, and Oxazoline functional groups was studied using quantum mechanical DFT methods at B3LYP-D3(BJ)/6-311 + g(d,p) theoretical level in water medium. The QTAIM, NBO, DOS, frontier orbital, conceptual-DFT indices, and non-covalent interaction analysis were further implemented to investigate the possible interactions between FP and Chit NPs. The results show that the adsorption of FP on Chit NPs is done through the creation of hydrogen bonds, and the highest absorption energy of - 18.15 kcal/mol between pristine chitosan and FP. In the case of all functionalized Chit NPs, a decrease in the absorption energy is observed, which is more noticeable in the case of N-acylated and O-acetyl functionalize Chit NPs, and indicates the weakening of the van der Waals interactions for these cases. Considering the compatibility of Chit NPs with the human body and their non-toxicity, as well as the fact that factors such as pH, solubility, the ionic strength, and so on can be adjusted to control the release rate using the functionalized Chit NPs, it seems that the results of this work can be a comprehensive guide to design the drug delivery methods of FP drug using Chit NPs, to reduce the symptoms of COVID-19 disease.


Association of norepinephrine transporter gene with methylphenidate response.
This study aimed to explore the association between alleles of the norepinephrine transporter gene and the methylphenidate response. Chinese Han youths with attention-deficit/hyperactivity disorder recruited in the Outpatient Department of the Institute of Mental Health from 2001 to 2004 were treated with methylphenidate in doses of 0.45 to 0.60 mg/kg per day. Behavior changes were measured by the ADHD Rating Scale-IV when optimal doses were reached. The single-nucleotide polymorphic allele of norepinephrine transporter gene G1287A was used as the genetic marker, and the genotypes were identified by restriction fragment length polymorphism analysis. A significant association was found between norepinephrine transporter gene G1287A genotypes and response to methylphenidate for hyperactive-impulsive subscale scores (mean score reduction was 7.15 and 6.94 for G/G and G/A genotype, respectively, and 2.13 for A/A; p = .012) but not inattentive scores. These findings suggest an association between the G1287A polymorphism of the norepinephrine transporter gene and variation in methylphenidate response. Further work is needed to confirm this finding and to assess its generalization to other ethnic groups.


Diagnostic approach to the solitary pulmonary nodule.
The number of solitary pulmonary nodules (SPNs) detected each year is expected to increase dramatically with the implementation of lung cancer screening. Although some will have radiographic features highly specific for benignity, the rest are considered indeterminate and require further investigation. The management options include continued surveillance or immediate diagnostic sampling. The decision to proceed with immediate sampling is determined by nodule characteristics (i.e., density and size), and patient risk factors and preferences. Sampling is achieved either by surgical or by nonsurgical techniques, and the choice between the two is influenced by the probability of malignancy. Surgical methods are preferred in SPNs with high probability of malignancy because they provide both a definitive diagnosis and treatment in a single procedure. In contrast, when the probability of malignancy is low to moderate nonsurgical sampling is preferred. The following is a review of the diagnostic management options available when approaching an SPN.


Glutamate/GABA co-release selectively influences postsynaptic glutamate receptors in mouse cortical neurons.
Cultured rat cortical neurons co-expressing VGLUT1 and VGAT (mixed synapses) co-release Glu and GABA. Here, mixed synapses were studied in cultured mouse cortical neurons to verify whether in mice mixed synapses co-release Glu and GABA, and to gain insight into how they may influence excitation/inhibition balance. Results showed the existence of synapses and autapses that co-release Glu and GABA in cultured mouse cortical neurons, and the ability of both neurotransmitters to evoke postsynaptic responses mediated by ionotropic receptors. We studied the short-term plasticity of glutamatergic, GABAergic, and mixed responses and we found that the kinetics of mixPSC amplitude depression was similar to that observed in EPSCs, but it was different from that of IPSCs. We found similar presynaptic release characteristics in glutamatergic and mixed synapses. Analysis of postsynaptic features, obtained by measuring AMPAR- and NMDAR-mediated currents, showed that AMPAR-mediated currents were significantly higher in pure glutamatergic than in mixed synapses, whereas NMDAR-mediated currents were not significantly different from those measured in mixed synapses. Overall, our findings demonstrate that glutamatergic and mixed synapses share similar electrophysiological properties. However, co-release of GABA and Glu influences postsynaptic ionotropic glutamatergic receptor subtypes, thus selectively influencing AMPAR-mediated currents. These findings strengthen the view that mixed neurons can play a key role in CNS development and in maintaining the excitation-inhibition balance.


Phase II trial of paclitaxel and granulocyte colony-stimulating factor in patients with pancreatic carcinoma: a Southwest Oncology Group study.
Pancreatic cancer is difficult to treat, with most patients surgically unresectable at the time of diagnosis. Radiotherapy and chemotherapy can offer palliation, but more effective therapy is needed. This trial evaluated the effects of an aggressive schedule of paclitaxel given with granulocyte colony-stimulating factor (G-CSF) to patients with advanced pancreatic cancer. All patients were required to have a histologic diagnosis of pancreatic adenocarcinoma with measurable disease and no prior chemotherapy or radiation therapy. Patients had to have performance status of 0 to 2, pretreatment absolute granulocyte count > or = 1,500/microL, and platelet count greater than or equal to the institutional lower limit of normal. Following pretreatment with dexamethasone, diphenhydramine, and cimetidine, patients received paclitaxel at a dose of 250 mg/m2 by 24-hour infusion on day 1, repeated every 21 days. G-CSF was given at a dose of 5 microg/kg/d on days 3 to 18 or until two consecutive absolute neutrophil counts (ANCs) > or = 10,000/microL were obtained. Doses of paclitaxel were modified depending on nadir counts. Forty-five patients were entered onto this study, with six ineligible. For the 39 eligible patients, there was one complete response (CR) and two partial responses (PRs), five stable/no responses, 23 increasing disease, two early deaths, and six patients whose assessment was inadequate to determine response. The response rate was therefore three of 39 or 8% (95% confidence interval [CI], 2% to 21%). The median survival time for the 39 eligible patients was 5 months. The most common toxicities were anemia, leukopenia/granulocytopenia, malaise/fatigue, nausea/vomiting, alopecia, thrombocytopenia, paresthesias, and liver function abnormalities. There was one death due to sepsis. Single-agent paclitaxel in this dose and schedule has minimal activity in pancreatic adenocarcinoma patients.


Can questions of the privatization and corporatization, and the autonomy and accountability of public hospitals, ever be resolved?
Although there is a long-standing international debate concerning the privatization and corporatization of health services, there has been relatively little systematic analysis of the ways these types of reform manifest. We examine the impact of privatization and corporatization on public hospitals, and in particular on hospitals' autonomy and accountability, with two aims: to uncover the key themes in the literature, and to consider implementation issues. The review of 2,319 articles was conducted using content analysis and a discussion of selected key issues. Several major themes appear in the privatization and corporatization literature, including their use as tools in health systems reform, and the role of governments in sponsoring the processes. We show that much of the underlying argument is ideological rather than evidence based. Those who promote versions of privatization or corporatization claim that decreased government involvement in the management of hospitals leads inter alia to benefits such as greater efficiency, better quality services, and increased choice for patients. Those who argue against say that increased privatization leads to deleterious outcomes such as decreased equity, compromised efficiency and poorer quality of care. The evidence is often weak and at times conflicting. Privatization and corporatization are difficult to implement, and at best produce mixed results, and their impact seems to depend more on the motivation of the evaluator than the standard of the results. These debates are of a type that is to a large extent only resolvable ideologically.


Free prostate-specific antigen improves prostate cancer detection in a high-risk population of men with a normal total PSA and digitalrectal examination.
Uncertainty exists regarding optimal prostate cancer screening parameters for high-risk populations. The purpose of this study is to report the use of percent free prostate-specific antigen (PSA) as an indication for biopsy in men at increased risk for developing prostate cancer who have a normal digital rectal examination (DRE) and total PSA level between 2 and 4 ng/mL. African-American men and men with at least one first-degree relative with prostate cancer are eligible for enrollment into the Prostate Cancer Risk Assessment Program (PRAP) at our institution. Between October 1996 and April 2002, 310 asymptomatic high-risk men with no history of prostate cancer, benign prostatic hyperplasia (BPH), or prostatic intraepithelial neoplasia (PIN) were screened in the PRAP with DRE and total PSA. Percent free PSA was obtained in men with a total PSA between 2 and 10 ng/mL. Men with a normal DRE and total PSA between 2 and 4 ng/mL were advised to undergo transrectal ultrasound-guided (TRUS) biopsies of the prostate if the percent free PSA was less than 27%. Other indications for biopsy included an abnormal DRE or a total PSA greater than 4 ng/mL. The primary endpoint evaluated was prostate cancer detection in high-risk men with a benign prostate examination, a normal total PSA between 2 and 4 ng/mL, and percent free PSA less than 27%. Of the 310 men, 174 (56%) were African American and 202 (65%) had at least one first-degree relative with prostate cancer. Sixty-two of the 310 men were referred for prostate biopsy, and 40 of 62 had biopsy performed. Twenty-one of 40 men were diagnosed with prostate cancer for a cancer detection rate of 53% in all men undergoing biopsy and an overall cancer detection rate of 6.8% in this high-risk population. Thirty-seven high-risk men (median age 54 years) with a total PSA level between 2 and 4 ng/mL (median 2.7 ng/mL) and a normal DRE were found to have a percent free PSA level of less than 27% (median 16%, range 8% to 25%). Twenty-three of these 37 men (62%) proceeded with the recommended prostate biopsy. Prostatic adenocarcinoma was diagnosed in 12 of 23 men for a cancer detection rate of 52% in men undergoing biopsy and 32% in all men with a normal DRE, a total PSA between 2 and 4 ng/mL, and a percent free PSA less than 27%. All positive biopsies demonstrated clinically significant Gleason score 6 or 7 disease. In all men electing radical prostatectomy, bilateral organ-confined disease (pT2bN0M0) was confirmed. In this unique population of men at high risk for prostate cancer, a percent free PSA of less than 27% was found to be useful for detecting early-stage but clinically significant cancers in men with a total PSA value between 2 and 4 ng/mL and normal DRE findings.


[Comparison of biochemical and Doppler sonographic monitoring of high-risk pregnancies].
We performed in 113 patients at least three simultaneous determinations of serum-HPL and oestriol in 24-hour urine samples, as well as Doppler flow studies at the arcuate artery (AA), umbilical artery (UA), foetal aorta and internal carotid, because of suspicion of IUGR. The diagnostic value was studied with regard to IUGR, placental weight and mode of delivery. Concerning the detection of IUGR, the superiority of Doppler parameters (AA, UA) is shown. In the total number of patients, the rates for sensitivity and specificity for UA (78/91%) and AA (58/89%) exceed the hormone parameters. Oestriol, in particular, (13/63%) shows a marked difference, but even HPL (37/63%) cannot compete with respect to diagnostic value.


Adaptation in temporally variable environments: stickleback armor in periodically breaching bar-built estuaries.
The evolutionary consequences of temporal variation in selection remain hotly debated. We explored these consequences by studying threespine stickleback in a set of bar-built estuaries along the central California coast. In most years, heavy rains induce water flow strong enough to break through isolating sand bars, connecting streams to the ocean. New sand bars typically re-form within a few weeks or months, thereby re-isolating populations within the estuaries. These breaching events cause severe and often extremely rapid changes in abiotic and biotic conditions, including shifts in predator abundance. We investigated whether this strong temporal environmental variation can maintain within-population variation while eroding adaptive divergence among populations that would be caused by spatial variation in selection. We used neutral genetic markers to explore population structure and then analysed how stickleback armor traits, the associated genes Eda and Pitx1 and elemental composition (%P) varies within and among populations. Despite strong gene flow, we detected evidence for divergence in stickleback defensive traits and Eda genotypes associated with predation regime. However, this among-population variation was lower than that observed among other stickleback populations exposed to divergent predator regimes. In addition, within-population variation was very high as compared to populations from environmentally stable locations. Elemental composition was strongly associated with armor traits, Eda genotype and the presence of predators, thus suggesting that spatiotemporal variation in armor traits generates corresponding variation in elemental phenotypes. We conclude that gene flow, and especially temporal environmental variation, can maintain high levels of within-population variation while reducing, but not eliminating, among-population variation driven by spatial environmental variation.


Brief Report: Malignancies in Adults Living With HIV in Asia.
Hematological malignancies have continued to be highly prevalent among people living with HIV (PLHIV). This study assessed the occurrence of, risk factors for, and outcomes of hematological and nonhematological malignancies in PLHIV in Asia. Incidence of malignancy after cohort enrollment was evaluated. Factors associated with development of hematological and nonhematological malignancy were analyzed using competing risk regression and survival time using Kaplan-Meier. Of 7455 patients, 107 patients (1%) developed a malignancy: 34 (0.5%) hematological [0.08 per 100 person-years (/100PY)] and 73 (1%) nonhematological (0.17/100PY). Of the hematological malignancies, non-Hodgkin lymphoma was predominant (n = 26, 76%): immunoblastic (n = 6, 18%), Burkitt (n = 5, 15%), diffuse large B-cell (n = 5, 15%), and unspecified (n = 10, 30%). Others include central nervous system lymphoma (n = 7, 21%) and myelodysplastic syndrome (n = 1, 3%). Nonhematological malignancies were mostly Kaposi sarcoma (n = 12, 16%) and cervical cancer (n = 10, 14%). Risk factors for hematological malignancy included age >50 vs. ≤30 years [subhazard ratio (SHR) = 6.48, 95% confidence interval (CI): 1.79 to 23.43] and being from a high-income vs. a lower-middle-income country (SHR = 3.97, 95% CI: 1.45 to 10.84). Risk was reduced with CD4 351-500 cells/µL (SHR = 0.20, 95% CI: 0.05 to 0.74) and CD4 >500 cells/µL (SHR = 0.14, 95% CI: 0.04 to 0.78), compared to CD4 ≤200 cells/µL. Similar risk factors were seen for nonhematological malignancy, with prior AIDS diagnosis showing a weak association. Patients diagnosed with a hematological malignancy had shorter survival time compared to patients diagnosed with a nonhematological malignancy. Nonhematological malignancies were common but non-Hodgkin lymphoma was more predominant in our cohort. PLHIV from high-income countries were more likely to be diagnosed, indicating a potential underdiagnosis of cancer in low-income settings.