AIDS and multidrug-resistant tuberculosis: an epidemic transforms an old disease.
Since 1985, tuberculosis case counts in the United States have increased, primarily because of the influence of the HIV epidemic. In addition, during this time outbreaks of multidrug-resistant tuberculosis among patients with AIDS or HIV infection have been reported in New York City and Florida. These outbreaks have occurred in hospitals and prisons and have been characterized by high case fatality rates, disease transmission within the institutions, and high infection rates in health care workers. The increase in tuberculosis rates and the outbreaks have raised concern that multidrug-resistant tuberculosis could become a widespread problem in the United States. Dealing with tuberculosis in the 1990s will require reconsideration of our current methods of tuberculosis prevention, diagnosis, treatment, and control.


Marital status and variability in cortisol excretion in postmenopausal women.
Based on the premise that acute and chronic stresses stimulate and suppress cortisol secretion, respectively, and the hypothesis that marriage provides a buffer to stress, we tested whether extreme values of serum cortisol concentrations would be less likely in married women than in unmarried women. Three hundred women were recruited from two central Connecticut communities. Cortisol was measured in overnight urine samples using liquid chromatography-tandem mass spectrometry. Information on each subject's demographic characteristics, such as income and education level was collected. Mean log urinary cortisol was virtually identical in married and unmarried women, however, as predicted, the variance was significantly larger in the unmarried group (p=0.01). After adjustment for potential confounders, multivariate logistic regression still revealed that absolute deviation of log(10) cortisol from the mean was smaller for married versus unmarried women (p<0.01); deviation from the mean cortisol was also higher for non-working than working women. These results support the idea that marriage and employment reduce the extreme levels of cortisol secretion, and by extension, this may reflect differences in levels of stress in married and in working women compared to unmarried and non-working women.


Effects of graded levels of bentonite on serum clinical profiles, metabolic hormones, and serum swainsonine concentrations in lambs fed locoweed (Oxytropis sericea).
To determine which clay minerals have the potential to bind swainsonine, an in vitro screening procedure was conducted. Twenty compounds were screened in one replicated in vitro trial. A commercially available bentonite bound approximately 10% swainsonine and was chosen for use in a subsequent lamb feeding trial. Twenty fine-wool lambs (30.5 +/- .7 kg) were assigned to one of five treatments (four lambs/treatment). Treatments included 1) positive control, 100% sorghum sudangrass hay, 2) 85% sorghum sudangrass:15% locoweed (Oxytropis sericea, 430 ppm [DM basis] of swainsonine) +0 g of bentonite, 3) Treatment 2 + 14 g of bentonite, 4) Treatment 2 + 28 g of bentonite, and 5) Treatment 2 + 42 g of bentonite. Lambs were fed the experimental diets for 35 d and were then fed the positive control diet for an additional 21 d. Lambs were weighted and blood was collected via jugular venipuncture weekly from d 0 through 56. On d 35, additional blood samples were collected 1, 2, 4, and 8 h after feeding. Weekly blood samples were analyzed for serum clinical chemistry profiles, and additional blood samples collected on d 35 were analyzed for serum metabolic hormones and serum swainsonine concentrations. Within 1 wk, serum alkaline phosphatase and glutamic oxaloacetic transaminase activities increased markedly (P < .05) in lambs fed locoweed. Serum insulin, growth hormone, and prolactin concentrations were not affected by feeding locoweed, but serum triiodothyronine and thyroxine concentrations were decreased by approximately 50% (P < .05) in lambs fed locoweed.(ABSTRACT TRUNCATED AT 250 WORDS)


Haematological parameters of parvovirus B19 infection in 13 fetuses with hydrops foetalis.
Thirteen cases of fetal parvovirus B19 infection with hydrops foetalis are reported. Viral DNA was identified by polymerase chain reaction (PCR) of amniotic fluid sampled between the 19th and the 29th week of gestation. Haematological examination revealed severe anaemia in all cases and thrombocytopenia in 11/13 cases, which was severe in two cases. Six fetuses died in utero; two after intrauterine transfusion. Complete recovery was observed in seven fetuses; five cases were treated by intrauterine transfusions, and in two cases spontaneous recovery occurred. Upon follow-up, no case of congenital anaemia was observed.


Experiences Among African American Community Members With Pharmacy-Based Immunization Services in Detroit, Michigan.
Background: Although vaccination rates improved modestly in the United States during the 2014-2015 season, racial and ethnic disparities in the use of vaccines persist. Pharmacy-based immunization programs expand access to immunization services; however, African Americans in one metropolitan community did not have the same level of access to this service as non-Hispanic whites. Objective: To examine the experiences of African Americans with pharmacy-based services and identify how pharmacies and pharmacy organizations can better service patients in urban communities with similar dynamics. Methods: This qualitative study utilized focus group discussions among African American residents in Detroit, Michigan, where there are reported disparities in access to pharmacists that immunize to learn more about their experiences with pharmacy-based immunization services. Results: Three major themes emerged: the pharmacy location is often more convenient and accessible than doctors' offices, there is clear communication with the pharmacist, and perceived lower immunization fees at pharmacies. Participants found pharmacies easier to access in their community for immunization services. Consistent interaction with familiar pharmacists and pharmacy staff members facilitated strong relationships and dialogue between pharmacists and patients. Patients perceived costs for vaccines to be less at the pharmacy than at their physicians' offices. Conclusions: Participants reported positive experiences with pharmacy-based immunization services and expansion of these services may influence more African Americans to receive recommended vaccines in this community.


MicroRNA‑494 inhibits apoptosis of murine vascular smooth muscle cells in vitro.
Apoptosis of vascular smooth muscle cells (VSMCs) is a process that regulates vessel remodeling in various cardiovascular diseases. The specific mechanisms that control VSMC apoptosis remain unclear. The present study aimed to investigate whether microRNA‑494 (miR‑494) is involved in regulating VSMC apoptosis and its underlying mechanisms. Cell death ELISA and terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling assays were used to detect apoptosis of murine VSMCs following stimulation with tumor necrosis factor‑α (TNF‑α). The results indicated that TNF‑α upregulated VSMC apoptosis in a dose‑dependent manner. Microarray analysis was used to evaluate the expression profile of microRNAs following TNF‑α stimulation in murine VSMCs. The expression of miR‑494 was downregulated, whereas B‑cell lymphoma-2‑like 11 (BCL2L11) protein expression levels were upregulated in VSMCs following treatment with TNF‑α. Luciferase reporter assays confirmed that BCL2L11 was a direct target of miR‑494. Transfection with miR‑494 mimics decreased VSMC apoptosis and downregulated BCL2L11 protein levels. Conversely, transfection with miR‑494 inhibitors increased cell apoptosis and upregulated BCL2L11 protein levels, suggesting that miR‑494 may function as an essential regulator of BCL2L11. The increase in apoptosis caused by miR‑494 inhibitors was abolished in cells co‑transfected with BCL2L11‑targeting small interfering RNA. The findings of the present study revealed that miR‑494 inhibited TNF‑α‑induced VSMC apoptosis by downregulating the expression of BCL2L11.


Glutathione Transferases as Efficient Ketosteroid Isomerases.
In addition to their well-established role in detoxication, glutathione transferases (GSTs) have other biological functions. We are focusing on the ketosteroid isomerase activity, which appears to contribute to steroid hormone biosynthesis in mammalian tissues. A highly efficient GST A3-3 is present in some, but not all, mammals. The alpha class enzyme GST A3-3 in humans and the horse shows the highest catalytic efficiency with kcat/Km values of approximately 107 M-1s-1, ranking close to the most active enzymes known. The expression of GST A3-3 in steroidogenic tissues suggests that the enzyme has evolved to support the activity of 3β-hydroxysteroid dehydrogenase, which catalyzes the formation of 5-androsten-3,17-dione and 5-pregnen-3,20-dione that are substrates for the double-bond isomerization catalyzed by GST A3-3. The dehydrogenase also catalyzes the isomerization, but its kcat of approximately 1 s-1 is 200-fold lower than the kcat values of human and equine GST A3-3. Inhibition of GST A3-3 in progesterone-producing human cells suppress the formation of the hormone. Glutathione serves as a coenzyme contributing a thiolate as a base in the isomerase mechanism, which also involves the active-site Tyr9 and Arg15. These conserved residues are necessary but not sufficient for the ketosteroid isomerase activity. A proper assortment of H-site residues is crucial to efficient catalysis by forming the cavity binding the hydrophobic substrate. It remains to elucidate why some mammals, such as rats and mice, lack GSTs with the prominent ketosteroid isomerase activity found in certain other species. Remarkably, the fruit fly Drosophila melanogaster, expresses a GSTE14 with notable steroid isomerase activity, even though Ser14 has evolved as the active-site residue corresponding to Tyr9 in the mammalian alpha class.


Rethinking global digital health and AI-for-health innovation challenges.
Digital health technologies can help tackle challenges in global public health. Digital and AI-for-Health Challenges, controlled events whose goal is to generate solutions to a given problem in a defined period of time, are one way of catalysing innovation. This article proposes an expanded investment framework for Global Health AI and digitalhealth Innovation that goes beyond traditional factors such as return on investment. Instead, we propose non monetary and non GDP metrics, such as Disability Adjusted Life Years or achievement of universal health coverage. Furthermore, we suggest a venture building approach around global health, which includes filtering of participants to reduce opportunity cost, close integration of implementation scientists and an incubator for the long-term development of ideas resulting from the challenge. Finally, we emphasize the need to strengthen human capital across a range of areas in local innovation, implementation-science, and in health services.


Insight into recent reforms and initiatives in Austria: implications for key stakeholders.
Pharmaceutical expenditure continued to rise steadily in Austria during the 1990s and early 2000s despite a variety of reforms. However, recent reforms and initiatives have moderated the growth rate. These initiatives include transparent pricing of new drugs and generics, greater restrictions on the prescribing of new drugs and voluntary price reductions. Alongside this, there have also been initiatives to enhance rational and efficient prescribing. The lack of published data makes it difficult to fully analyze the impact of individual reforms. In addition, some reforms have only recently been introduced. Despite this, implications can be drawn for key stakeholder groups in the future. This includes pharmaceutical companies continuing to need to demonstrate substantially added benefit for their new drug to command average European prices. Otherwise, premiums will be restricted to a maximum 10% above the price of current standards. In addition, companies will need to continue to lower the price of their brands in interchangeable classes as standards become available as generics. The alternative will be prescribing restrictions. Further reforms will be needed in Austria to meet government growth targets for pharmaceutical expenditure of only 3-4% per annum, while continuing to fund new innovative drugs and increased volumes with greater prevalence of chronic diseases. Possible future measures and their implications for key stakeholder groups will also be discussed.


Anterior decompression and interbody fusion with BAK/C for cervical disc degenerative disorders.
A retrospective clinical study of 64 patients who underwent anterior cervical discectomy and fusion (ACDF) with BAK/C for disc degenerative disorders. To evaluate the long-term outcome of BAK/C in the treatment of cervical disc degenerative disorders. ACDF has been demonstrated to be effective in the treatment of cervical disc degenerative disorders. BAK/C, a kind of thread cage widely used for interbody fusion in the lumbar spine, was used in the cervical spine to avoid the donor site complications of traditional autologous bone graft. Sixty-four patients with cervical disc degenerative disorders underwent ACDF with BAK/C technique in our institution between September 1997 and December 2000. All the patients were followed up for at least 6 years. The changes of segmental stability, bone fusion, cervical lordosis, and intervertebral height on radiographs were evaluated in detail immediately after operation, at 6 and 12 months postoperatively, and yearly thereafter. The clinical outcome of neurologic improvement and pain relief was also investigated. Solid fusion was achieved at 1 year postoperatively in all patients, and the segmental stability was maintained during the whole follow-up. The cervical lordosis and intervertebral height were well restored immediately after operation, and gradually lost during the follow-up. Especially, the anterior height of intervertebral space decreased significantly after 1 year, when compared with the anterior height immediately after operation. BAK/C subsidence was observed in 9 patients, including 5 with 1-level fusion, 1 with 2-separated-level fusion, and 3 with 2-adjacent-level fusion, according to the standard of loss of intervertebral height more than 3 mm. BAK/C fusion was generally effective in the treatment of cervical disc degenerative disorders, according to the evaluation of neurologic improvement and pain relief. However, neck pain tended to reoccur in the patients with cage subsidence, and 2 of them even needed revision surgery because of the recurrence of myelopathy and progressive neck pain. Although BAK/C technique was generally effective and safe in the treatment of cervical disc degenerative disorders, the pitfalls of cage design resulted in the disability of maintenance of cervical lordosis and intervertebral height in the long-term follow-up. Cage subsidence, which tended to develop in the patients with 2-level fusion, was possibly responsible for the recurrence of neck pain.


The Amyloid Fibril-Forming β-Sheet Regions of Amyloid β and α-Synuclein Preferentially Interact with the Molecular Chaperone 14-3-3ζ.
14-3-3 proteins are abundant, intramolecular proteins that play a pivotal role in cellular signal transduction by interacting with phosphorylated ligands. In addition, they are molecular chaperones that prevent protein unfolding and aggregation under cellular stress conditions in a similar manner to the unrelated small heat-shock proteins. In vivo, amyloid β (Aβ) and α-synuclein (α-syn) form amyloid fibrils in Alzheimer's and Parkinson's diseases, respectively, a process that is intimately linked to the diseases' progression. The 14-3-3ζ isoform potently inhibited in vitro fibril formation of the 40-amino acid form of Aβ (Aβ40) but had little effect on α-syn aggregation. Solution-phase NMR spectroscopy of 15N-labeled Aβ40 and A53T α-syn determined that unlabeled 14-3-3ζ interacted preferentially with hydrophobic regions of Aβ40 (L11-H21 and G29-V40) and α-syn (V3-K10 and V40-K60). In both proteins, these regions adopt β-strands within the core of the amyloid fibrils prepared in vitro as well as those isolated from the inclusions of diseased individuals. The interaction with 14-3-3ζ is transient and occurs at the early stages of the fibrillar aggregation pathway to maintain the native, monomeric, and unfolded structure of Aβ40 and α-syn. The N-terminal regions of α-syn interacting with 14-3-3ζ correspond with those that interact with other molecular chaperones as monitored by in-cell NMR spectroscopy.


High Fat High Sugar Diet Reduces Voluntary Wheel Running in Mice Independent of Sex Hormone Involvement.
Introduction: Indirect results in humans suggest that chronic overfeeding decreases physical activity with few suggestions regarding what mechanism(s) may link overfeeding and decreased activity. The primary sex hormones are known regulators of activity and there are reports that chronic overfeeding alters sex hormone levels. Thepurpose of this study was to determine if chronic overfeeding altered wheel running through altered sex hormone levels. Materials and Methods: C57BL/6J mice were bred and the pups were weaned at 3-weeks of age and randomly assigned to either a control (CFD) or high fat/high sugar (HFHS) diet for 9-11 weeks depending on activity analysis. Nutritional intake, body composition, sex hormone levels, and 3-day and 2-week wheel-running activity were measured. Additionally, groups of HFHS animals were supplemented with testosterone (males) and 17β-estradiol (females) to determine if sex hormone augmentation altered diet-induced changes in activity. Results: 117 mice (56♂, 61♀) were analyzed. The HFHS mice consumed significantly more calories per day than CFD mice (male: p < 0.0001; female: p < 0.0001) and had significantly higher body fat (male: p < 0.0001; female: p < 0.0001). The HFHS diet did not reduce sex hormone levels, but did significantly reduce acute running-wheel distance in male (p = 0.05, 70 ± 28%) and female mice (p = 0.02, 57 ± 26%). In animals that received hormone supplementation, there was no significant effect on activity levels. Two-weeks of wheel access was not sufficient to alter HFHS-induced reductions in activity or increases in body fat. Conclusion: Chronic overfeeding reduces wheel running, but is independent of the primary sex hormones.


The validity of continuing developmental follow-up of high-risk infants to age 5 years.
We conducted a study to determine whether performance on developmental tests at age 5 years could predict academic achievement at age 8 years. As part of a longitudinal developmental surveillance project, 179 children at risk due to perinatal complications who had passed developmental screening through age 2 1/2 years and 50 comparison children underwent an extensive prekindergarten psychoeducational test battery at age 5 years and took the Iowa Tests of Basic Skills at age 8 years, if they had reached the third grade. The mean Iowa Tests of Basic Skills score was significantly lower for those children who were "flagged" on the prekindergarten psychoeducational test battery (t = 5.39). Preacademic, rather than developmental, items appeared to be the best predictors. However, the prekindergarten psychoeducational test battery correctly predicted low achievement or grade retention in only 58% of cases. Its sensitivity was 0.45 and its specificity was 0.85. No significant difference was noted between group Iowa Tests of Basic Skills mean scores for the high-risk or comparison group. When low achievement and failure to reach the third grade were combined, prevalence of "failure" was higher for the high-risk group (31% vs 24%). The only perinatal variable predictive of low achievement was neonatal seizures. In summary, because the ability to predict future academic achievement at age 5 years is limited, routine developmental testing for symptom-free preschool children is not warranted. High-risk infant follow-up programs should focus on the first several years of life.


Alkaline phosphatase as a periodontal disease marker.
The potential of alkaline phosphatase (ALP) as an important diagnostic marker of gingival crevicular fluid (GCF) has been the subject to investigation since 1970. ALP is stored in specific granules and secretory vesicles of the neutrophils and is mainly released during their migration to the site of infection. It is also present in bacteria within dental plaque, osteoblasts and fibroblasts. It has, thus, become important to elucidate whether GCF levels of ALP are potential measures of the inflammatory activity occurring in the adjacent periodontal tissues. The aim of this study was to assess the total activity of ALP in the GCF collected from healthy sites, sites with gingivitis and with chronic adult periodontitis. An attempt was also made to establish the correlation of ALP activity with plaque index, gingival index, bleeding index and probing depth. A total of 18 patients were divided into three groups: viz., healthy sites, Group I; gingivitis, Group II; chronic periodontitis, Group III. Clinical parameters like plaque index, bleeding index, gingival index and probing depth were recorded. The ALP level in GCF of all three groups was determined by spectrophotometric analysis. Total enzyme activity of ALP was significantly higher in periodontitis as compared with that in healthy and gingivitis sites, and was significantly and positively correlated with probing depth. ALP can be considered as a periodontal disease marker as it can distinguish between healthy and inflamed sites. However, to better define its capacity for periodontal diagnosis, additional longitudinal studies are required.


Further psychometric validation of the BODY-Q: ability to detect change following bariatric surgery weight gain and loss.
Recent systematic reviews have identified that current patient-reported outcome instruments have content limitations when used to measure change following bariatric surgery. The aim of this study was to measure change after bariatric surgery using the BODY-Q, a PRO instrument designed for weight loss and body contouring. The BODY-Q is composed of 18 independently functioning scales and an obesity-specific symptom checklist that measure appearance, health-related quality of life (HR-QOL) and experience of health-care. The sample for this study included patients who were exploring or seeking bariatric surgery in Hamilton (Canada) at the time of the BODY-Q field-test study and who agreed to further contact from the research team. These patients were invited to complete 12 BODY-Q scales and the symptom checklist between 7 June 2016 and 29 November 2016. Data were collected online (REDCap) and via postal surveys. Clinical change was measured using paired t-tests with effect sizes and standardized response means. The survey was completed by 58 of 89 (65%) pre-bariatric participants from the original BODY-Q field-test sample. The non-participants did not differ from participants in terms of age, gender, ethnicity, BMI or initial BODY-Q scale scores. Participants who had undergone bariatric surgery had a mean BMI of 49 (SD = 7) at time 1 and 35 (SD = 7) at time 2. Time since bariatric surgery was on average 2 years (SD = 0.5) (range 0.4 to 3 years). Percentage total weight loss ranged from 12 to 51 (mean 31, SD = 9). The difference in the proportion of patients to report an obesity-specific symptom on the BODY-Q checklist was significantly lower at follow-up for 5 of 10 symptoms. Participants improved on BODY-Q scales measuring appearance (of abdomen, back, body, buttocks, hips/outer thighs, inner thigh), body image and physical function (p < 0.001 on paired t-tests) and social function (p = 0.002 on paired t-test). These changes were associated with moderate to large effect sizes (0.60 to 2.29) and standardized response means (0.47 to 1.35). The BODY-Q provides a set of independently functioning scales that measure issues important to patients who undergo weight loss. BODY-Q scales were responsive to measuring clinical change associated with weight loss 2 years after bariatric surgery.


Evaluation of neonatal mortality in Buenos Aires City by place of residence and use of a health system subsector.
Neonatal mortality is the most important component of infant mortality. Analyzing neonatal mortality is complex and does not depend exclusively on the health system. In Buenos Aires City (CABA), between2000 and 2012, neonatal mortality rate was lower than the national mean rate but no changes were recorded. Besides, the difference is narrowing: in 2000, it was 46% lower but in 2012, it was 21% lower. To assess the relationship among the place of maternal residence, the use of a health system subsector, and mortality rate among newborn infants younger than 28 days old in CABA. Cross-sectional, population-based study conducted in 2011 and 2012 using data from the Office of Vital Records and the Department of Statistics and Surveys of CABA. A total of 164 837 births were recorded. The ratio of births in public and private facilities has remained stable; the private subsector accounts for 57% ofbirths. The ratiobetweenbothsubsectors was also similar in terms of gender, birthweight, and average gestational age. Neonatal mortalitywas higher among mothers who lived outside CABA (6.55%o versus 5.42%, odds ratio: 1.21, 95% confidence interval: 1.07-1.37, p 0.0039). Among mothers living in CABA, neonatal mortality was higher in the public health subsector (7.8% versus 4.4%, odds ratio: 1.77, 95% confidence interval: 1.48-2.11, p < 0.001). Unlike any other district in Argentina, CABA has a very high rate of births and deaths from other jurisdictions, especially from Greater Buenos Aires, which is not reflected in official statistics that only consider the place of parental residence.


Activation of protein kinase C by lysophosphatidic acid: dependence on composition of phospholipid vesicles.
Lysophosphatidic acid (LPA) has attracted recent attention as a major serum-derived regulator implicated in responses to vascular injury and inflammation, in tumour invasiveness and in neuronal signalling and remodelling. Although the possibility of a specific G-protein-coupled LPA receptor protein has been suggested, characterization of such a receptor is lacking. Since LPA can activate protein kinase C (PKC) pathways in many cells and PKC activators mimic many LPA effects, the possibility of more direct LPA effects on PKC was investigated. Phosphatidylcholine (PC)/phosphatidylserine (PS)/diacylglycerol (DAG) lipid vesicles of defined acyl chain composition were used to activate the enzyme. At total concentrations of saturated PC/PS + DAG vesicles (2-3 mM) that provided maximal PKC activation, 1-10 mol % [18:1]-LPA led to a further approx. 2-fold activation of PKC alpha. At lower lipid concentrations, a greater increase was observed with LPA concentrations up to 16-20 mol %. Higher concentrations of LPA were inhibitory. The LPA activation of PKC was dependent on the presence of DAG, PS and Ca2+. [18:1]-Lysophosphatidylcholine produced similar PKC activation in PC/PS/DAG vesicles. [14:0]-LPA was less effective, and longer-chain saturated lysolipids were ineffective. In unsaturated PC/PS vesicles, very little to no effect of LPA was discernable. These results suggest that physiologically or pathologically relevant concentrations of LPA can contribute to PKC activation depending on the composition of the lipid membrane. We hypothesize that LPA may affect the formation of lipid domains that are recognized by the enzyme.


[The blood serum systems in patients with tuberculosis].
Phenotypes of haptoglobin (Hp), group-specific proteins (Gc), transferrins and ceruloplasmin were studied by means of polyacrylamide gel disk electrophoresis of serum proteins in 411 tuberculosis patients and 283 apparently healthy individuals living in the North-West and Extreme North. Regardless of their ethnic affiliation, tuberculosis patients tend to accumulate Hp 2-2, Gc 1-1 carriers and Hp 2-2 + Gc 1-1 combinations. The persons with the above types of individual proteins usually have a serious clinical picture of the disease and lower activity of the immune T-system, as confirmed by different methods of multidimensional statistical analysis. Hp 2-2, Gc 1-1 carriers and Hp 2-2 and Gc 1-1 combinations among the Extreme North's healthy aboriginal population are more widespread than among the healthy inhabitants of the North-West.


[Experience of anesthesia during transthoracic endoscopic sympathectomy for palmar hyperhidrosis: comparison between double-lumen endobronchial tube ventilation and laryngeal mask ventilation].
In the past year we had 36 patients operated for transthoracic endoscopic sympathectomy to treat palmar hyperhidrosis. The first group composed of 17 patients receiving anesthesia with double-lumen endobronchial-tube ventilation from July-92 to April-93, and the second group composed of 19 patients receiving anesthesia with laryngeal mask ventilation from April-93 to August-93. During right lung collapse for sympathectomy, the first group patients' SaO2 (oxygen saturation) decreased from 99.65 +/- 0.62 mmHg (pre-operation) to 95.12 +/- 5.48 mmHg (at cauterization), 95.24 +/- 5.41 mmHg (5 minutes after cauterization) and resumed 99.53 +/- 0.62 mmHg after the procedure completed. During left lung collapse for left side sympathectomy, the same group patients' SaO2 decreased from 99.59 +/- 0.62 mmHg to 97.35 +/- 3.06 mmHg, 97.82 +/- 2.53 mmHg and resumed 99.65 +/- 0.49 mmHg respectively. The second group using laryngeal mask ventilation had SaO2 changes during right side sympathectomy from 99.68 +/- 0.58 mmHg (pre-cauterization) to 99.74 +/- 0.45 mmHg (when cauterization), 99.79 +/- 0.42 mmHg (5 minutes after cauterization) and resumed 99.84 +/- 0.37 mmHg after the procedure completed. During left side sympathectomy the second group patients' SaO2 changed from 99.84 +/- 0.39 mmHg to 99.42 +/- 1.50 mmHg, 99.47 +/- 1.46 mmHg and resumed 99.74 +/- 0.59 mmHg respectively. After 2-Way ANOVA with repeated measures of the SaO2 value, we could see that no matter what side operation, there were differences existed between these two groups (< 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Disseminated candidiasis in addicts who use brown heroin: report of 83 cases and review.
From November 1983 to April 1990, disseminated candidiasis was diagnosed in 83 heroin addicts at our institution. All patients had consumed brown heroin diluted in fresh lemon juice. Sixty-two (75%) had skin lesions, 41 (49%) had ocular lesions, and 35 (42%) had one or several costochondral tumors. Candida albicans was grown in culture or histopathologically identified in 34 cases (41%). The patients who had only cutaneous lesions were treated with ketoconazole, and they were all cured. The patients with ocular involvement received systemic amphotericin B with or without oral flucytosine; 29 of these patients developed varying degrees of vision loss. The method of treatment of costochondral tumors was not uniform; in 14 cases the lesions were resected. The one patient who died developed endocarditis involving the aortic valve. Cases of pleuropulmonary involvement, spondylitis, and large-joint arthritis have also been described among the 300 cases reported in the reviewed literature. This is a new syndrome of candidal infection in drug addicts who use brown heroin; ocular lesions are the most harmful manifestation, and loss of vision is the major sequela.


Determinants and aetiologies of postpartum pyrexia; a retrospective analysis in a tertiary health facility in the Littoral Region of Cameroon.
Postpartum febrile morbidity is relatively common, occurring in approximately 5-7% of births. Differentiating between potentially serious and benign causes of postpartum pyrexia (PP) is fundamental in curbing the mortality rate from sinister causes such as sepsis. The paucity of data on PP in Cameroon makes it difficult to access its actual burden. This study was aimed at determining the prevalence, risk factors and aetiologies of PP at a tertiary hospital in Douala, Cameroon. This was a 2 - year hospital - based retrospective cohort study carried out at the Douala General Hospital (DGH), during which medical records of all postpartum admissions between January 1st 2017 and December 31st 2018 were reviewed. The review consisted of collecting data on socio-demographic characteristics, clinical profile, investigations and final diagnoses. The collected data was analysed in SPSS 23.0. Chi-squared test was used to test the association between variables and a logistic regression analysis was fitted to identify risk factors associated to PP. A total of 1520 postpartum files were reviewed. The prevalence of PP was 8.82%. The most frequent causes of PP were: malaria (46.7%), urinary tract infections (18.7%), puerperal sepsis (17.9%) and pneumonia (8.7%). E. coli was the most (49.3%) cultured germ isolated in positive cultures. Onset of PP was more common (85%) within the first 3 days postpartum and malaria (60%) was the leading aetiology within this period. Five or more vaginal examinations prior to delivery (OR 59.151, 95% CI: 21.463-163.019; p < 0.001), perineal tears (OR 45.157, 95% CI: 2.266-899.722; p < 0.001), and duration of labour > 18 h (OR 26.760, 95% CI: 7.100-100.862; p < 0.001) were the most significant risk factors associated with PP. Approximately 1 in every 12 postpartum cases in the DGH presents with PP. Malaria was the leading cause of PP at DGH especially for cases registered within 3 days postpartum. The risk factors identified were mostly associated to perinatal events, such as frequent vaginal examinations, perineal tears and prolonged labour. Efforts towards preventing identified risk factors thus becomes paramount in order to curb this high rate of PP in the DGH.


The Louisiana Amphibian Monitoring Program from 1997 to 2017: Results, analyses, and lessons learned.
To determine trends in either frog distribution or abundance in the State of Louisiana, we reviewed and analyzed frog call data from the Louisiana Amphibian Monitoring Program (LAMP). The data were collected between 1997 and 2017 using North American Amphibian Monitoring Program protocols. Louisiana was divided into three survey regions for administration and analysis: the Florida Parishes, and 2 areas west of the Florida parishes called North and South. Fifty-four routes were surveyed with over 12,792 stops and 1,066 hours of observation. Observers heard 26 species of the 31 species reported to be in Louisiana. Three of the species not heard were natives with ranges that did not overlap with survey routes. The other two species were introduced species, the Rio Grande Chirping Frog (Eleutherodactylus cystignathoides) and the Cuban Treefrog (Osteopilus septentrionalis). Both seem to be limited to urban areas with little to no route coverage. The 15 most commonly occurring species were examined in detail using the percentage of stops at which they observed along a given survey and their call indices. Most species exhibited a multimodal, concave, or convex pattern of abundance over a 15-year period. Among LAMP survey regions, none of the species had synchronous population trends. Only one group of species, winter callers, regularly co-occur. Based on the species lists, the North region could be seen as a subset of the South. However, based on relative abundance, the North was more similar to Florida parishes for both the winter and summer survey runs. Our analyses demonstrate that long-term monitoring (10 years or more) may be necessary to determine population and occupancy trends, and that frog species may have different local demographic patterns across large geographic areas.


[In vitro vasculogenesis and angiogenesis of mouse embryonic stem cells].
To explore an optional condition to induce mouse embryonic stem (ES) cells to differentiate into endothelial cells and to establish in vitro models of vasculogenesis and angiogenesis. Mouse ES cells were cultured in differentiation medium containing a cocktail of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-6 (IL-6) and erythropoietin (EPO) in 1% methylcellulose to induce formation of embryoid bodies (EBs). At day 11, EBs were harvested and suspended in rat-tail collagen type I with the same cocktail of cytokines cultured for three additional days. The differentiation of ES cells into endothelial cells, processes of vasculogenesis and angiogenesis were examined using immunostaining of EBs slices and whole-mount immunocytochemistry of EBs with monoclonal antibodies (mAbs) against platelet endothelial cell adhesion molecule-1 (PECAM-1) and alpha-smooth muscle actin (SMA). Under appropriate culture conditions; ES cells spontaneously differentiated and formed EBs containing vascular structures and tubular channels, which were positive for PECAM-1 co-differentiated with smooth muscle. When not treated with angiogenic growth factors, PECAM-1-positive cells could not organize into vascular structures of 11-day-old EBs. In the presence of angiogenic factors 11-day old EBs embedded into type I collagen, and rapidly developed an endothelial networks. Whole-mount immunocytochemistry of collagen gel with anti-PECAM-1 antibody showed the formation of primary vascular structures sprouting from EBs. Quantitative analysis revealed that 100 microg/ml thalidomide significantly reduced the number and length of EBs endothelial sprouting. Mouse ES cells can differentiate into endothelial cells combined with smooth muscle differentiation during EBs formation and further develop endothelial outgrowths after EBs embedded into collagen, which respectively recapitulate vasculogenesis, angiogenesis, and arteriogenesis processes in vivo. The models provide a useful tool to investigate vasculogenesis, angiogenesis, and arteriogenesis mechanisms and evaluate the effects of angiogenic and angiostatic agents.


Progress and perspectives on directing group-assisted palladium-catalysed C-H functionalisation of amino acids and peptides.
Peptide modifications can unlock a variety of compounds with structural diversity and abundant biological activity. In nature, peptide modifications, such as functionalisation at the side-chain position of amino acids, are performed using post-translational modification enzymes or incorporation of unnatural amino acids. However, accessing these modifications remains a challenge for organic chemists. During the past decades, selective C-H activation/functionalisation has attracted considerable attention in synthetic organic chemistry as a pathway to peptide modification. Various directing group strategies have been discovered that assist selective C-H activation. In particular, bidentate directing groups that enable tuneable and reversible coordination are now recognised as one of the most efficient methods for the site-selective C-H activation and functionalisation of numerous families of organic compounds. Synthetic peptide chemists have harnessed bidentate directing group strategies for selective functionalisation of the β- and γ-positions of amino acids. This method has been expanded and recognised as an effective device for the late stage macrocyclisation and total synthesis of complex peptide natural products. In this review, we discuss various β-, γ-, and δ-C(sp3)-H bond functionalisation reactions of amino acids for the formation of C-X bonds with the aid of directing groups and their application in late-stage macrocyclisation and the total synthesis of complex peptide natural products.


Chronic lymphocytic leukaemia in the cat: 18 cases (2000-2010).
There is little information regarding the presentation, biologic behaviour, treatment and prognosis in cats with chronic lymphocytic leukaemia (CLL), and further investigation is needed to characterize this disease in cats. The goal of this study was to describe the clinical presentation, response to treatment and prognosis of feline CLL. A multi-institutional retrospective study of 18 cats diagnosed with CLL between 2000 and 2010 was performed. CLL was defined as the presence of a mature lymphocytosis (>9000 lymphocytes µL(-1) ) and confirmation of an immunophenotypically monomorphic or clonal lymphoid population. Each patient was required to also have at least one of the two following criteria: (1) concurrent cytopenia of at least one cell line and/or (2) >15% mature lymphocytes in the bone marrow. Data on signalment, history, clinical signs, clinicopathologic features and response to treatment were reviewed. Median age of the cats at initial presentation was 12.5 years (range: 5-20 years). The most common presenting complaint was chronic weight loss, which was present in 8/18 (44%) cats. Sixteen of 18 (89%) cats were treated with chlorambucil and prednisolone; four of these cats also received vincristine. Two (11%) cats were treated with multi-agent injectable chemotherapy (L-CHOP, l-asparaginase, cyclophosphamide, doxorubicin, vincristine, prednisolone). Eighty-eight percent of cats evaluable for response achieved a complete (nine cats) or partial (six cats) remission. Median overall remission was 15.7 months (range: 1.3-22.8 months). The median overall survival in the 17 cats with follow-up data was 14.4 months (range: 0.9-25.3 months). Results of this study suggest that CLL affects older-aged cats and responds favourably to treatment with oral chlorambucil and prednisolone.


Potentiometric, electronic structural, and ground- and excited-state optical properties of conjugated bis[(porphinato)zinc(II)] compounds featuring proquinoidal spacer units.
We report the synthesis, optical, electrochemical, electronic structural, and transient optical properties of conjugated (porphinato)zinc(II)-spacer-(porphinato)zinc(II) (PZn-Sp-PZn) complexes that possess intervening conjugated Sp structures having varying degrees of proquinoidal character. These supermolecular PZn-Sp-PZn compounds feature Sp moieties {(4,7-diethynylbenzo[c][1,2,5]thiadiazole (E-BTD-E), 6,13-diethynylpentacene (E-PC-E), 4,9-diethynyl-6,7-dimethyl[1,2,5]thiadiazolo[3,4-g]quinoxaline (E-TDQ-E), and 4,8-diethynylbenzo[1,2-c:4,5-c']bis([1,2,5]thiadiazole) (E-BBTD-E)} that regulate frontier orbital energy levels and progressively increase the extent of the quinoidal resonance contribution to the ground and electronically excited states, augmenting the magnitude of electronic communication between terminal (5,-10,20-di(aryl)porphinato)zinc(II) units, relative to that evinced for a bis[(5,5',-10,20-di(aryl)porphinato)zinc(II)]butadiyne benchmark (PZnE-EPZn). Electronic absorption spectra show significant red-shifts of the respective PZn-Sp-PZn x-polarized Q state (S0 --> S1) transition manifold maxima (240-4810 cm(-1)) relative to that observed for PZnE-EPZn. Likewise, the potentiometrically determined PZn-Sp-PZn HOMO-LUMO gaps (E1/2(0/+) - E1/2(-/0)) display correspondingly diminished energy separations that range from 1.88 to 1.11 eV relative to that determined for PZnE-EPZn (2.01 eV). Electronic structure calculations provide insight into the origin of the observed PZn-Sp-PZn electronic and optical properties. Pump-probe transient spectral data for these PZn-Sp-PZn supermolecules demonstrate that the S1 --> S(n) transition manifolds of these species span an unusually broad spectral domain of the NIR. Notably, the absorption maxima of these S1 --> S(n) manifolds can be tuned over a 1000-1600 nm spectral region, giving rise to intense excited-state transitions approximately 4000 cm(-1) lower in energy than that observed for the analogous excited-state absorption maximum of the PZnE-EPZn benchmark; these data highlight the unusually large quinoidal resonance contribution to the low-lying electronically excited singlet states of these PZn-Sp-PZn species. The fact that the length scales of the PZn-Sp-PZn species (approximately 25 angstrom) are small with respect to those of classic conducting polymers, yet possess NIR S1 --> S(n) manifold absorptions lower in energy, underscore the unusual electrooptic properties of these conjugated structures.


The 3-T Model of Informed Consent for Nonstandard Risk Donors: A Proposal for Transplant Clinical Practice.
The risk of disease transmission from nonstandard risk donors (NSRDs) is low, and outcomes are similar or better relative to transplants performed with standard criteria donors. However, NSRDs have posed new ethical challenges to the informed consent (IC) process. Based on the shared decision-making model, coinciding with the 3 main timings of the IC process ([1] pretransplant assessments and waiting list registration, [2] time on the waiting list, and [3] time of the organ offer), we put forward a model (3-T Model) to summarize the knowledge on IC for NSRDs and to deliver conceptual and practical support to transplant providers on this emergent issue. We searched PubMed and analyzed data from our area to provide evidence and ethical arguments to promote standardization of the timing of patient information, degree of patient participation, and disclosure of donor risk factors throughout the 3 stages of the time continuum leading to the potential acceptance of NSRDs. Each of the 3 timings carries special ethical significance and entails well-defined duties for transplant providers relative to patient involvement and information of the benefits and risks associated with NSRDs. Based on our framework, experience, and interpretation of the literature, we put forward a list of recommendations to combine standardization (ie, timing, content, and degree of patient participation) and individualization of IC. The 3-T Model may enable the prevention of physicians' arbitrariness and the promotion of patient-centered care. Future studies will assess the effectiveness of the 3-T Model in transplant clinical practice.


Near-infrared -triggered release of tirofiban from nanocarriers for the inhibition of platelet integrin αIIbβ3 to decrease early-stage neointima formation.
Platelets play an important role in the early stage of arterial remodeling after injury. Integrin GPIIb/IIIα (αIIbβ3) regulates platelet activation in the inside-out and outside-in signaling pathways. The use of tirofiban, an integrin αIIbβ3 inhibitor, in clinical therapy is limited by its short in vivo circulation time. Herein, a controlled drug-release system was formulated using CuS@mSiO2-PEG core-shell nanoparticles as near-infrared-triggered nanocarriers to release tirofiban on demand. The nanocarriers possessed good colloidal stability and very high loading efficiency for the integrin αIIbβ3 inhibitor (14.5 wt% for tirofiban). Local application of αIIbβ3 antagonist-tirofiban on an injured arterial wall inhibited platelet activation, which was accelerated by laser irradiation. Ex vivo platelet-promoted monocyte transmigration trans-well assays revealed decreased monocyte transmigration after platelet activation was inhibited by tirofiban. Two weeks after the wire-induced injury, the intimal area and cellular content were analyzed. The neointimal area was decreased in ApoE-/- mice with CuS@mSiO2-PEG/tirofiban and laser irradiation-promoted tirofiban release, which had limited the neointima formation. The lesions showed a decreased content of macrophages and smooth muscle cells compared with ApoE-/- mice without tirofiban inhibition. Therefore, the action of platelet-integrin αIIbβ3 in neointima formation after vascular injury was successfully inhibited in vivo through the controlled release of tirofiban using a near-infrared-triggered nanocarrier, leading to the decrease of early-stage neointima formation. This study also emphasizes the role of platelets in vascular remodeling and provides a new target, namely integrin αIIbβ3, for the inhibition of neointimal hyperplasia during vascular inflammation.


Effects of collection time and food consumption on the urine protein/creatinine ratio in the dog.
Effects of collection time and food consumption on the variability of the urine protein/creatinine ratio were determined in 10 healthy dogs. In trial 1, dogs were fasted for 12 hours, and urine specimens were obtained by bladder catheterization every 2 hours over an 8-hour collection period during the day. After a 1-week rest, the dogs were entered into trial 2. Dogs were fed at least 60 kcal of a high protein meal/kg of body weight, and urine specimens were obtained every 2 hours over an 8-hour period during the day. Urine total protein and urine creatinine concentrations and the urine protein/creatinine ratio were determined for each urine specimen obtained. Friedman's 2-way analysis by ranks was used to determine the constancy of this ratio over the 4 periods in the 2 trials (fasted and fed). There was no significant variability (P greater than 0.05) in ratios over the 8-hour collection periods in the fasted or fed trial. Feeding did not significantly alter this ratio, because there was no significant difference (P greater than 0.05) in the urine protein/creatinine ratios of the dogs when they were fasted, compared with those of the dogs when they were fed. Seemingly, urine specimens obtained anytime during the day from dogs in both trials (fasted and fed) reflected the urine protein/creatinine ratio.


Phosphatidylcholine embedded micellar systems: enhanced permeability through rat skin.
Micellar and microemulsion systems are excellent potential vehicles for delivery of drugs because of their high solubilization capacity and improved transmembrane bioavailability. Mixtures of propylene glycol (PG) and nonionic surfactants with sodium diclofenac (DFC) were prepared in the presence of phosphatidylcholine (PC) as transmembrane transport enhancers. Fully dilutable systems with maximum DFC solubilization capacity (SC) at pH 7 are presented. It was demonstrated that the concentrates underwent phase transitions from reverse micelles to swollen reverse micelles and, via the bicontinuous transitional mesophase, into inverted O/W microstructures. The SC decreases as a function of dilution. DFC transdermal penetration using rat skin in vitro correlated with SC, water content, effect of phospholipid content, presence of an oil phase, and ethanol. Skin penetration from the inverted bicontinuous mesophase and the skin penetration from the O/W-like microstructure were higher than that measured from the W/O-like droplets, especially when the micellar system containing the nonionic surfactant, sugar ester L-1695, and hexaglycerol laurate. PC embedded within the micelle interface significantly increased the penetration flux across the skin compared to micellar systems without the embedded PC at their interface. Moreover, the combination of PC with HECO40 improved the permeation rate (P) and shortened the lag-time (T(L)).


Heritability of corticosterone response and changes in life history traits during selection in the zebra finch.
Vertebrates respond to environmental stressors through the neuro-endocrine stress response, which involves the production of glucocorticoids. We have selected independent, duplicate divergent lines of zebra finches for high, low and control corticosterone responses to a mild stressor. This experiment has shown that over the first four generations, the high lines have demonstrated a significant realized heritability of about 20%. However, the low lines have apparently not changed significantly from controls. This asymmetry in response is potentially because of the fact that all birds appear to be showing increased adaptation to the environment in which they are housed, with significant declines in corticosterone response in control lines as well as low lines. Despite the existence of two- to threefold difference in mean corticosterone titre between high and low lines, there were no observed differences in testosterone titre in adult male birds from the different groups. In addition, there were no consistent, significant differences between the lines in any of the life history variables measured--number of eggs laid per clutch, number of clutches or broods produced per pair, number of fledglings produced per breeding attempt, nor in any of egg, nestling and fledgling mortality. These results highlight the fact that the mechanisms that underlie variation in the avian physiological system can be modified to respond to differences between environments through selection. This adds an additional level of flexibility to the avian physiological system, which will allow it to respond to environmental circumstances.


Hyperopic thermal keratoplasty procedure in a civilian air traffic controller.
Hyperopic thermal keratoplasty (HTK), also referred to as radial thermokeratoplasty, is one of several refractive surgery procedures in use to correct significant visual acuity problems. The current procedure was developed in the farmer Soviet Union, and was first performed in the U.S. in the early 1980's. The thermocoagulating unit used for the surgery is still considered an experimental device by the Food and Drug Administration, and as such requires a device exemption permit from that Agency for its use. The unit is used to coagulate corneal protein, which alters the shape of the cornea and hence its refractive power. No well-controlled series of patients followed over time exists to conclusively state the pros and cons of the procedure. Excimer laser surgery has been recently used as a substitute for the thermocoagulator, but experience is also limited. Lasers, nevertheless, show great promise for use in this procedure. While HTK has been shown to correct hyperopia, significant sequelae have been documented with the procedure; they have included unstable visual acuity, under- and overcorrection of acuity, damage to the cornea, and scarring. These sequelae may present a problem for individuals involved in aviation, where issues of visual acuity are critical. It is important to identify such individuals and monitor their vision status carefully prior to return to safety related duties.


Cross-sectional study of aortic valve calcification and cardiovascular risk factors in older Danish men.
Aortic valve calcification (AVC) and coronary artery calcification (CAC) are predictors of cardiovascular disease (CVD), presumably sharing risk factors. Our objectives were to determine the prevalence and extent of AVC in a large population of men aged 60-74 years and to assess the association between AVC and cardiovascular risk factors including CAC and biomarkers. Participants from the DANish CArdioVAscular Screening and intervention trial (DANCAVAS) with AVC and CAC scores and without previous valve replacement were included in the study. Calcification scores were calculated on non-contrast CT scans. Cardiovascular risk factors were self-reported, measured or both, and further explored using descriptive and regression analysis for AVC association. 14 073 men aged 60-74 years were included. The AVC scores ranged from 0 to 9067 AU, with a median AVC of 6 AU (IQR 0-82). In 8156 individuals (58.0%), the AVC score was >0 and 215 (1.5%) had an AVC score ≥1200. In the regression analysis, all cardiovascular risk factors were associated with AVC; however, after inclusion of CAC ≥400, only age (ratio of expected counts (REC) 1.07 (95% CI 1.06 to 1.09)), hypertension (REC 1.24 (95% CI 1.09 to 1.41)), obesity (REC 1.34 (95% CI 1.20 to 1.50)), known CVD (REC 1.16 (95% CI 1.03 to 1.31)) and serum phosphate (REC 2.25 (95% CI 1.66 to 3.10) remained significantly associated, while smoking, diabetes, hyperlipidaemia, estimated glomerular filtration rate and serum calcium were not. AVC was prevalent in the general population of men aged 60-74 years and was significantly associated with all modifiable cardiovascular risk factors, but only selectively after adjustment for CAC ≥400 AU. NCT03946410 and ISRCTN12157806.


Anesthesia and colorectal cancer - The perioperative period as a window of opportunity?
Gastrointestinal malignancies largely contribute to cancer related deaths in the United States, with colorectal cancer representing the 3rd place of the ten leading entities of mortality due to cancer for both females and males. The majority of patients with GI tumors has to undergo surgery (either as a curative or palliative intervention) and are therefore also in need for a proper general and/or regional anesthesia. Recent findings have suggested that the type of anesthesia administered might have an impact on cancer recurrence and metastasis and thus this new field in the anesthesia world has become a largely studied topic. This review highlights current concepts and summarizes the evidence for an impact of the type of anesthesia on patient outcome after cancer surgery, suggesting the perioperative period might be a "window of opportunity" which should not be missed.


The organisation of the efferent projections of the zona incerta.
The hypothesis that the six cytoarchitectonically distinct subdivisions of the zona incerta send efferent projections to different parts of the brain was tested using retrograde fluorescent tracing techniques. Injections of tracer in the superior colliculus, pontomesencephalic tegmentum, thalamus or spinal cord resulted in characteristic and distinctive patterns of labelling in the zona incerta, suggesting that the different subdivisions of the zona incerta give rise to different sets of efferent projections. Thus, injections into the deep layers of the superior colliculus resulted in retrogradely labelled neurons predominantly in the zona incerta pars ventralis, whereas injections into the pontomesencephalic tegmentum, avoiding the superior colliculus, labelled neurons mostly in the zona incerta pars dorsalis. Parafascicular thalamic injections resulted in labelled neurons in the zona incerta pars rostropolaris, pars dorsalis, pars caudalis and a few in the pars ventralis. The spinal cord injections labelled predominantly the magnocellular cells of the zona incerta. The results of the double labelling experiment also give support to the conclusion that different areas of the zona incerta give rise to largely individual sets of efferent projections. Combined injections of tracers into the superior colliculus and thalamus resulted in the labelling of two essentially independent cell groups, the tectal projecting cells being found mainly in the zona incerta pars ventralis and the thalamic projecting cells being found in the zona incerta pars rostropolaris, pars dorsalis and pars caudalis. However, a small number of double labelled cells was found. These cells, which presumably send collateral projections to both the tectum and the thalamus, were found mainly in the dorsal part of the zona incerta pars ventralis, immediately next to the pars dorsalis. In the light of these findings it would appear that the zona incerta may be organised into largely distinct subdivisions, each of which has its own set of cytoarchitectonic and efferent projection characteristics.


Scalable method to produce biodegradable nanoparticles that rapidly penetrate human mucus.
Mucus typically traps and rapidly removes foreign particles from the airways, gastrointestinal tract, nasopharynx, female reproductive tract and the surface of the eye. Nanoparticles capable of rapid penetration through mucus can potentially avoid rapid clearance, and open significant opportunities for controlled drug delivery at mucosal surfaces. Here, we report an industrially scalable emulsification method to produce biodegradable mucus-penetrating particles (MPP). The emulsification of diblock copolymers of poly(lactic-co-glycolic acid) and polyethylene glycol (PLGA-PEG) using low molecular weight (MW) emulsifiers forms dense brush PEG coatings on nanoparticles that allow rapid nanoparticle penetration through fresh undiluted human mucus. In comparison, conventional high MW emulsifiers, such as polyvinyl alcohol (PVA), interrupts the PEG coating on nanoparticles, resulting in their immobilization in mucus owing to adhesive interactions with mucus mesh elements. PLGA-PEG nanoparticles with a wide range of PEG MW (1, 2, 5, and 10 kDa), prepared by the emulsification method using low MW emulsifiers, all rapidly penetrated mucus. A range of drugs, from hydrophobic small molecules to hydrophilic large biologics, can be efficiently loaded into biodegradable MPP using the method described. This readily scalable method should facilitate the production of MPP products for mucosal drug delivery, as well as potentially longer-circulating particles following intravenous administration.


Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment.
Testosterone (T) deficiency (TD) may significantly affect sexual function and multiple organ systems. To provide recommendations and Standard Operating Procedures (SOPs) based on best evidence for diagnosis and treatment of TD in men. Medical literature was reviewed by the Endocrine subcommittee of the ISSM Standards Committee, followed by extensive internal discussion over two years, then public presentation and discussion with other experts. Recommendations and SOPs based on grading of evidence-based medical literature and interactive discussion. TD is the association of a low serum T with consistent symptoms or signs. T level tends to decline with age. T modulates sexual motivation and erection. It also plays a broader role in men's health. Recent studies have established associations between low T, male sexual dysfunctions and metabolic risk factors. Though association does not mean causation, low T is associated with reduced longevity, risk of fatal cardiovascular events, obesity, sarcopenia, mobility limitations, osteoporosis, frailty, cognitive impairment, depression, Sleep Apnea Syndrome, and other chronic diseases. The paper proposes a standardized process for diagnosis and treatment of TD, and updates the knowledge on T therapy (Tth) and prostate and cardiovascular safety. There is no compelling evidence that Tth causes prostate cancer or its progression in men without severe TD. Polycythemia is presently the only cardiovascular-related adverse-event significantly associated with Tth. But follow-up of controlled T trials is limited to 3 years. Men with sexual dysfunctions, and/or with visceral obesity and metabolic diseases should be screened for TD and treated. Young men with TD should also be treated. Benefits and risks of Tth should be carefully assessed in older men. Prospective, long-term, placebo-controlled, interventional studies are required before screening for TD in more conditions, including cardiovascular diseases, and considering correction of TD as preventive medicine.


Dynamic causal modelling of EEG and fMRI to characterize network architectures in a simple motor task.
Dynamic causal modelling (DCM) has extended the understanding of brain network dynamics in a variety of functional systems. In the motor system, DCM studies based on functional magnetic resonance imaging (fMRI) or on magneto-/electroencephalography (M/EEG) have demonstrated movement-related causal information flow from secondary to primary motor areas and have provided evidence for nonlinear cross-frequency interactions among motor areas. The present study sought to investigate to what extent fMRI- and EEG-based DCM might provide complementary and synergistic insights into neuronal network dynamics. Both modalities share principal similarities in the formulation of the DCM. Thus, we hypothesized that DCM based on induced EEG responses (DCM-IR) and on fMRI would reveal congruent task-dependent network dynamics. Brain electrical (63-channel surface EEG) and Blood Oxygenation Level Dependent (BOLD) signals were recorded in separate sessions from 14 healthy participants performing simple isometric right and left hand grips. DCM-IR and DCM-fMRI were used to estimate coupling parameters modulated by right and left hand grips within a core motor network of six regions comprising bilateral primary motor cortex (M1), ventral premotor cortex (PMv) and supplementary motor area (SMA). We found that DCM-fMRI and DCM-IR similarly revealed significant grip-related increases in facilitatory coupling between SMA and M1 contralateral to the active hand. A grip-dependent interhemispheric reciprocal inhibition between M1 bilaterally was only revealed by DCM-fMRI but not by DCM-IR. Frequency-resolved coupling analysis showed that the information flow from contralateral SMA to M1 was predominantly a linear alpha-to-alpha (9-13Hz) interaction. We also detected some cross-frequency coupling from SMA to contralateral M1, i.e., between lower beta (14-21Hz) at the SMA and higher beta (22-30Hz) at M1 during right hand grip and between alpha (9-13Hz) at SMA and lower beta (14-21Hz) at M1 during left hand grip. In conclusion, the strategy of informing EEG source-space configurations with fMRI-derived coordinates, cross-validating basic connectivity maps and analysing frequency coding allows for deeper insight into the motor network architecture of the human brain. The present results provide evidence for the robustness of non-invasively measured causal information flow from secondary motor areas such as SMA towards M1 and further contribute to the validation of the methodological approach of multimodal DCM to explore human network dynamics.


Studies of mice lacking plasminogen activator gene function suggest that plasmin production prior to ovulation exceeds the amount needed for optimal ovulation efficiency.
Many studies suggest that the plasminogen activator (PA) system plays a role in the proteolytic degradation of the follicle wall at the time of ovulation. Consistently, the ovulation efficiency is reduced by 26% in mice where both physiological PA genes have been inactivated. To reveal the mechanism behind reduced ovulation efficiency in PA-deficient mice and its effect on ovarian proteolysis. we have studied the regulation of plasmin activity in the ovaries of 25-day-old wild-type mice and mice with deficient PA gene function during gonadotropin-induced ovulation. In wild-type mice the plasmin activity was low in ovarian extracts from mice treated with pregnant mare's serum gonadotropin. However, this activity was increased between 2-8 h after an ovulatory dose of human choriogonadotropins. In mice lacking either tissue-type PA (tPA) or PA inhibitor type 1 (PAI-1) the plasmin activity levels prior to ovulation were similar to wild-type mice, while extracts prepared from urokinase-type PA (uPA) deficient mice had 10% or less of the plasmin activity. This indicates that most of the plasmin activity in the mouse ovary is generated by uPA. In addition, as the ovulation efficiency is impaired in tPA/uPA-deficient mice but appears normal in uPA-deficient mice, our data indicates that the amount of plasmin generated by PAs prior to ovulation in wild-type mice greatly exceeds the amount required for efficient ovulation.


Examination of real-time fluctuations in suicidal ideation and its risk factors: Results from two ecological momentary assessment studies.
Two studies examined 2 important but previously unanswered questions about the experience of suicidal ideation: (a) How does suicidal ideation vary over short periods of time?, and (b) To what degree do risk factors for suicidal ideation vary over short periods and are such changes associated with changes in suicidal ideation? Participants in Study 1 were 54 adults who had attempted suicide in the previous year and completed 28 days of ecological momentary assessment (EMA; average of 2.51 assessments per day; 2,891 unique assessments). Participants in Study 2 were 36 adult psychiatric inpatients admitted for suicide risk who completed EMA throughout their time in the hospital (average stay of 10.32 days; average 2.48 assessments per day; 649 unique assessments). These studies revealed 2 key findings: (a) For nearly all participants, suicidal ideation varied dramatically over the course of most days: more than 1-quarter (Study 1 = 29%; Study 2 = 28%) of all ratings of suicidal ideation were a standard deviation above or below the previous response from a few hours earlier and nearly all (Study 1 = 94.1%; Study 2 = 100%) participants had at least 1 instance of intensity of suicidal ideation changing by a standard deviation or more from 1 response to the next. (b) Across both studies, well-known risk factors for suicidal ideation such as hopelessness, burdensomeness, and loneliness also varied considerably over just a few hours and correlated with suicidal ideation, but were limited in predicting short-term change in suicidal ideation. These studies represent the most fine-grained examination of suicidal ideation ever conducted. The results advance the understanding of how suicidal ideation changes over short periods and provide a novel method of improving the short-term prediction of suicidal ideation. (PsycINFO Database Record


HBsAg seropositive status and survival after renal transplantation: meta-analysis of observational studies.
The natural history of hepatitis B virus (HBV) infection after renal transplantation (RT) remains unclear. We conducted a systematic review of the published medical literature on the impact of HBV surface antigen (HBsAg) seropositivity on survival of RT recipients. We used the random effects model of DerSimonian and Laird to generate a summary estimate of the relative risk for mortality and graft loss in HBsAg positive RT recipients across the published studies. We identified six observational studies (6050 unique patients); all of them being cohort, retrospective studies. Pooling of study results demonstrated that HBsAg in serum was an independent and significant risk factor for death after RT; the summary estimate for relative risk was 2.49 with a 95% confidence interval (95% CI) of 1.64-3.78. A test for homogeneity of the relative risk across the studies gave a p-value of <0.0001. HBsAg seropositivity was an independent and significant risk factor for graft failure after RT; the summary estimate was 1.44 with a 95% CI of 1.02-2.04 (homogeneity test, p <0.0001). This meta-analysis shows that HBsAg positive RT recipients have an increased risk for mortality and graft failure compared to seronegative patients.


Molecular characterization of extended-spectrum-β-lactamase-producing and plasmid-mediated AmpC β-lactamase-producing Escherichia coli isolated from stray dogs in South Korea.
A total of 47 extended-spectrum-cephalosporin-resistant Escherichia coli strains isolated from stray dogs in 2006 and 2007 in the Republic of Korea were investigated using molecular methods. Extended-spectrum β-lactamase (ESBL) and AmpC β-lactamase phenotypes were identified in 12 and 23 E. coli isolates, respectively. All 12 ESBL-producing isolates carried bla(CTX-M) genes. The most common CTX-M types were CTX-M-14 (n = 5) and CTX-M-24 (n = 3). Isolates producing CTX-M-3, CTX-M-55, CTX-M-27, and CTX-M-65 were also identified. Twenty-one of 23 AmpC β-lactamase-producing isolates were found to carry bla(CMY-2) genes. TEM-1 was associated with CTX-M and CMY-2 β-lactamases in 4 and 15 isolates, respectively. In addition to bla(TEM-1), two isolates carried bla(DHA-1), and one of them cocarried bla(CMY-2). Both CTX-M and CMY-2 genes were located on large (40 to 170 kb) conjugative plasmids that contained the insertion sequence ISEcp1 upstream of the bla genes. Only in the case of CTX-M genes was there an IS903 sequence downstream of the gene. The spread of ESBLs and AmpC β-lactamases occurred via both horizontal gene transfer, accounting for much of the CTX-M gene dissemination, and clonal spread, accounting for CMY-2 gene dissemination. The horizontal dissemination of bla(CTX-M) and bla(CMY-2) genes was mediated by IncF and IncI1-Iγ plasmids, respectively. The clonal spread of bla(CMY-2) was driven mainly by E. coli strains of virulent phylogroup D lineage ST648. To our knowledge, this is the first report of bla(DHA-1) in E. coli strains isolated from companion animals. This study also represents the first report of CMY-2 β-lactamase-producing E. coli isolates from dogs in the Republic of Korea.


Mechanisms of improved specificity of engineered Cas9s revealed by single-molecule FRET analysis.
Cas9 (from Streptococcus pyogenes) in complex with a guide RNA targets complementary DNA for cleavage. Here, we developed a single-molecule FRET analysis to study the mechanisms of specificity enhancement of two engineered Cas9s (eCas9 and Cas9-HF1). A DNA-unwinding assay showed that mismatches affect cleavage reactions through rebalancing the unwinding-rewinding equilibrium. Increasing PAM-distal mismatches facilitates rewinding, and the associated cleavage impairment shows that cleavage proceeds from the unwound state. Engineered Cas9s depopulate the unwound state more readily with mismatches. The intrinsic cleavage rate is much lower for engineered Cas9s, preventing cleavage from transiently unwound off-targets. Engineered Cas9s require approximately one additional base pair match for stable binding, freeing them from sites that would otherwise sequester them. Therefore, engineered Cas9s achieve their improved specificity by inhibiting stable DNA binding to partially matching sequences, making DNA unwinding more sensitive to mismatches and slowing down the intrinsic cleavage reaction.


Potentiation of a primary in vivo antibody response by alloantisera against gene products of the I region of the H-2 complex.
Mice were immunized intravenously with suboptimal numbers (3.5-5 X 10(5)) of sheep erythrocytes together with various anti-Ia antisera or with sheep erythrocytes alone, and the primary IgM and IgG plaque-forming cell responses were assayed 6 days later9 A/J (H-2a) mice given 5 X 10(5) sheep erythrocytes together with as little as 0.4 mul of a (129 X A.TH)F1 anti-A.TL (anti-Iak) antiserum developed 2-3 times as many IgM and IGG plaque-forming cells as mice injected with antigen alone or together with various antisera not containing anti-Ia antibodies. Similar results were obtained with BALB/c (H-2d) mice and a (C3H X LG/Ckc)F1 anti-C3H. OH (anti-Iad) antiserum plus sheep erythrocytes. In the case of the anti-Iad antiserum, the potentiating activity could be absorbed with C3H. OH (Id) but not C3H(Ik) spleen cells, demonstrating that the active antibodies were specific for the Id region. Antiserum to I-Jk subregion-coded determinants was tested in A/J (I-Jk) mice and found to also potentiate 2- to 3-fold the plaque-forming cell response to suboptimal erythrocyte immunization. This antiserum [(BIO.A(3R) X DBA/2)F1 anti-B10.(5R)] failed to potentiate responses in BALB/c (I-Jd) mice, as expected on a genetic basis. The potentiating antibodies could be removed by absorption with B10.BR (I-Jk) but not B10 (I-Jb) spleen cells, also confirming the I-J specificity of the activity. The interference of anti-I-J antibodies with T lymphocyte suppressor mechanisms is prposed as a possible explanation for this phenomenon.


Fine particulate organic material in the Los Angeles Basin-I: assessment of the high-volume Brigham Young University organic sampling system, BIG BOSS
A multi-system, high-volume, parallel plate diffusion denuder Brigham Young University Organic Sampling System (BIG BOSS) was tested using collocated samplers at the Pico Rivera Monitoring Station of the South Coast Air Quality Management District, South Coast Air Basin, in September 1994. Six-hr daytime and 9-hr nighttime samples were collected with a flow of about 200 L/min through each of the three systems designed to collect particles smaller than 2.5, 0.8, and 0.4 microns in a diffusion denuder sampler. Efficiency for the removal of gas phase organic compounds by the diffusion denuder was evaluated using both theoretical predictions and field measurements. Both measured and calculated data indicate high denuder efficiency for the removal of gas phase aromatic and paraffinic compounds. The precision of the BIG BOSS was evaluated using collocated samplers. The precision of determination of total carbon and elemental carbon retained by a quartz filter or of semi-volatile carbonaceous material lost from particles during sampling averaged +/- 7%. The precision of determination of individual organic compounds averaged +/- 10%. An average of 42 and 62% of the particulate organic material was semi-volatile organic compounds (SVOCs) lost from particles during sampling for daytime and nighttime samples, respectively. This "negative" sampling artifact was an order of magnitude larger than the "positive" quartz filter artifact due to adsorption of gas phase organic material. Daytime concentrations of fine particulate elemental carbon and nonvolatile organic carbon were higher than nighttime concentrations, but nighttime fine particles contained more semi-volatile organic material than daytime.


Using MSK Ultrasound in the Evaluation of Subscapularis Injuries.
The shoulder is an area that can be prone to a variety of injuries, including subscapularis tendon tears. The subscapularis muscle is one of the four muscles that make up the rotator cuff in the shoulder and plays an essential role in stabilizing the shoulder joint while at the same time facilitating internal rotation of the humerus. Injuries to the subscapularis can occur due to trauma, overuse, or degeneration, leading to pain, weakness, and limited mobility. When injury occurs, subscapularis tendon tears are often difficult to diagnose and evaluate due to their location deep within the shoulder joint. While traditional imaging techniques like radiographs, and magnetic resonance imaging may give us insight into the structures present, they do not always provide detailed enough information for clinicians. Ultrasound has become increasingly popular in musculoskeletal (MSK) rehabilitation as it allows for direct visualization of soft tissue abnormalities like tendinopathies or subtle rotator cuff tear patterns. In this Ultrasound Bites article, we will discuss how MSK ultrasound can be used in the evaluation of subscapularis tendon pathology with a specific focus on its utility in the physical therapy clinic.


Tailored polyimide as positive electrode and polyimide-derived carbon as negative electrode for sodium ion full batteries.
Organic electrode materials have secured a distinctive place among the auspicious choices for modern energy storage systems due to their resource sustainability and environmental friendliness. Herein, a novel all-organic electrode-based sodium ion full battery is demonstrated using 1,4,5,8-naphthalenetetracarboxylic dianhydride (NTCDA) as raw material for the assembly of positive and negative electrodes. Both the electrodes exhibit excellent cycling stability and rate performance. The fabricated organic sodium ion full battery not only displays a high initial capacity of 157 mA h g-1 with an average battery voltage of 1.47 V under the current density of 100 mA g-1, but also delivers a high energy density of 254 W h kg-1 and a high power density of 614 W kg-1. These sodium ion batteries with organic positive and negative electrode materials can provide a new way for energy storage devices.


The HSUS's Pain and Distress Initiative: overview and update.
The Humane Society of the United States (HSUS) publicly launched its Pain and Distress Initiative in 2000, to encourage greater attention to the prevention and alleviation of pain and distress in research animals. The initiative's ultimate goal is the phasing out of all significant pain and distress in animal research by 2020. There have been several developments to date. A survey conducted for The HSUS revealed that Americans strongly oppose the use of animals in experiments that cause them to suffer. The HSUS has begun producing a newsletter, The Pain & Distress Report, distributed periodically to over 2000 Institutional Animal Care and Use Committees, scientists and regulators. In 2000, the US Department of Agriculture issued a proposal to upgrade the regulation and reporting of pain and distress. We have challenged the leading research institutions over their under-reporting of unrelieved pain and distress in animals. We have written a comprehensive critique of CO2 euthanasia, arguing that it causes avoidable pain and distress in animals. The National Institutes of Health has issued new guidance on CO2 euthanasia. These developments lay the groundwork for a sustained effort to eliminate animal suffering in research.


Endogenous dopamine and endocannabinoid signaling mediate cocaine-induced reversal of AMPAR synaptic potentiation in the nucleus accumbens shell.
Repeated exposure to drugs of abuse alters the structure and function of neural circuits mediating reward, generating maladaptive plasticity in circuits critical for motivated behavior. Within meso-corticolimbic dopamine circuitry, repeated exposure to cocaine induces progressive alterations in AMPAR-mediated glutamatergic synaptic transmission. During a 10-14 day period of abstinence from cocaine, AMPAR signaling is potentiated at synapses on nucleus accumbens (NAc) medium spiny neurons (MSNs), promoting a state of heightened synaptic excitability. Re-exposure to cocaine during abstinence, however, rapidly reverses and depotentiates enhanced AMPAR signaling. To understand how re-exposure to cocaine alters AMPAR synaptic transmission, we investigated the roles of dopamine and endocannabinoid (eCB) signaling in modifying synaptic strength in the NAc shell. Using patch-clamp recordings from NAc slices prepared after 10-14 days of abstinence from repeated cocaine, we found that AMPAR-mediated depotentiation is rapidly induced in the NAc shell within 20 min of cocaine re-exposure ex vivo, and persists for up to five days before synapses return to levels of potentiation observed during abstinence. In cocaine-treated animals, global dopamine receptor activation was both necessary and sufficient for the cocaine-evoked depotentiation of AMPAR synaptic function. Additionally, we identified that CB1 receptors are engaged by endogenous endocannabinoids (eCBs) during re-exposure to cocaine ex vivo. Overall, these results indicate the central role that dopamine and eCB signaling mechanisms play in modulating cocaine-induced AMPAR plasticity in the NAc shell.


Blocking mu-opioid receptors inhibits social bonding in rituals.
Religious rituals are universal human practices that play a seminal role in community bonding. In two experiments, we tested the role of mu-opioids as the active factor fostering social bonding. We used a mu-opioid blocker (naltrexone) in two double-blind studies of rituals from different religious traditions. We found the same effect across both studies, with naltrexone leading to significantly lower social bonding compared with placebo. These studies suggest that mu-opioids play a significant role in experiences of social bonding within ritual contexts.


Visual field defects in ocular hypertension and glaucoma.
We measured visual fields using three unconventional test stimuli; sine-wave grating targets of 2 and 5 cycles/degree and a visual acuity target. Of 15 patients with ocular hypertension (OHT), eight had visual field defects for contrast sensitivity when tested with a sine-wave grating target of low spatial frequency; these patients had normal perimetric fields and normal fields for visual acuity. We hypothesize that the outer extremities of the largest dendritic trees of retinal ganglion cells become functionally ineffective in some patients with OHT and early glaucoma, possibly due to retinal ischemia, and as a result visual sensitivity to low spatial frequency gratings is reduced while visual acuity is spared. Since this hypothetical mechanism may be somewhat independent of the mechanism that causes ganglion cell loss, not all the contrast field defects in OHT would be expected to progress to glaucomatous field defects and be evident to clinical perimetry.


NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with interleukin-2 (IL-2) and CTLA-4 blockade.
Melanoma is one of the few types of cancer with an increasing annual incidence. While a number of immunotherapies for melanoma have been associated with significant clinical benefit, including high-dose IL-2 and cytotoxic T lymphocyte antigen 4 (CTLA-4) blockade, clinical response to either of these single agents has been limited to 11-20% of treated patients. Therefore, in this study, we sought to test the hypothesis that the combination of IL-2 and CTLA-4 blockade could mediate a more profound therapeutic response. Here, B6 mice were challenged with poorly immunogenic B16 melanoma on day 0, and treated with CTLA-4 blocking antibody (100 μg/mouse) on days 3, 6, and 9, and IL-2 (100,000 units) twice daily on days 4-8, or both. A highly significant synergistic effect that delayed tumor growth and prolonged survival was demonstrated with the combination immunotherapy compared to either monotherapy alone. The therapeutic effect of combination immunotherapy was dependent on both CD8+ T and NK cells and co-depletion of these subsets (but not either one alone) abrogated the therapeutic effect. CTLA-4 blockade increased immune cell infiltration (including CD8+ T cells and NK cells) in the tumor and IL-2 reduced the proportion of highly differentiated/exhausted tumor-infiltrating NK cells. These results have implications for the design of clinical trials in patients with metastatic melanoma and provide new insights into how the immune system may be mediating anti-tumor activity with combination IL-2 and CTLA-4 blockade in melanoma.


MR-Guided Focused Ultrasound Central Lateral Thalamotomy for Trigeminal Neuralgia. Single Center Experience.
Background: Trigeminal neuralgia (TN) is a recognized pain condition the treatment of which can be very challenging. Various surgical interventions can be applied in cases of therapy-resistance to drug treatments. The central lateral thalamotomy (CLT) against neurogenic (or neuropathic) pain is based on multiarchitectonic histological as well as physiopathological studies, and integrates the nucleus in a large thalamocortical (TC) and corticocortical network responsible for the sensory, cognitive and affective/emotional components of pain. The advent of the magnetic resonance imaging guided high intensity focused ultrasound (MRgFUS) brought a strong reduction in morbidity and increase in accuracy compared to penetration techniques. Objective: This study was aimed at analyzing the outcome of bilateral MRgFUS CLT for chronic therapy-resistant trigeminal pain, all performed in one single center. Methods: Patients were categorized in Classical, Idiopathic and Secondary TN. By definition, paroxysms lasted for seconds up to 2 min. All patients were screened for trigeminal neurovascular conflict. In case of classical TN, microvascular decompression was proposed. Therapy-resistance and thus indication for MRgFUS CLT was based on the lack of efficacy and/or side effects of antiepileptic and antidepressant drugs. Good outcome was defined by a pain relief ≥50%. Results: Eight patients suffering from chronic therapy-resistant trigeminal neuralgia were treated. All suffered from pain with paroxysmal character. Six patients reported additionally continuous pain. Mean follow-up was 53 months (range: 12-92, median: 60 months). The mean pain relief assessed by patients was 51% (median: 58%, range: 0-90%) at 3 months, 71% (median: 65%, range: 40-100%) at 1 year and 78% (median: 75%, range: 50-100%) at their longest follow-up. This represents 63% good outcomes at 3 months, 88% at 1 year and 100% at last follow-up. Frequency of the mean pain paroxysms decreased from 84 per day preoperative to 3.9 at 1 year postoperatively. There were no serious adverse events in this series. Conclusion: Our study provides preliminary support for the safety and efficacy of MRgFUS CLT, a histologically and pathophysiologically based medial thalamotomy against chronic therapy-resistant trigeminal neuralgia.


Experimental evaluation of neutron dose in radiotherapy patients: Which dose?
The evaluation of peripheral dose has become a relevant issue recently, in particular, the contribution of secondary neutrons. However, after the revision of the Recommendations of the International Commission on Radiological Protection, there has been a lack of experimental procedure for its evaluation. Specifically, the problem comes from the replacement of organ dose equivalent by the organ-equivalent dose, being the latter "immeasurable" by definition. Therefore, dose equivalent has to be still used although it needs the calculation of the radiation quality factor Q, which depends on the unrestricted linear energy transfer, for the specific neutron irradiation conditions. On the other hand, equivalent dose is computed through the radiation weighting factor wR, which can be easily calculated using the continuous function provided by the recommendations. The aim of the paper is to compare the dose equivalent evaluated following the definition, that is, using Q, with the values obtained by replacing the quality factor with wR. Dose equivalents were estimated in selected points inside a phantom. Two types of medical environments were chosen for the irradiations: a photon- and a proton-therapy facility. For the estimation of dose equivalent, a poly-allyl-diglicol-carbonate-based neutron dosimeter was used for neutron fluence measurements and, additionally, Monte Carlo simulations were performed to obtain the energy spectrum of the fluence in each point. The main contribution to dose equivalent comes from neutrons with energy higher than 0.1 MeV, even when they represent the smallest contribution in fluence. For this range of energy, the radiation quality factor and the radiation weighting factor are approximately equal. Then, dose equivalents evaluated using both factors are compatible, with differences below 12%. Quality factor can be replaced by the radiation weighting factor in the evaluation of dose equivalent in radiotherapy environments simplifying the practical procedure.


Knowledge-based systems.
First developed two decades ago, knowledge-based systems have seen widespread application in recent years. While performance has been a strong focus of attention, building such systems has also expanded our conception of a computer program from a black box providing an answer to something capable of explaining its answers, acquiring new knowledge, and transferring knowledge to students. These abilities derive from distinguishing clearly what the program knows from how that knowledge will be used, making it possible to use the same knowledge in different ways.


[Coronary vasomotor response to acetylcholine correlates with plasma levels of cyclosporin and triglycerides in patients with heart transplantation].
Vasoconstriction of normal coronary arteries has been reported after intracoronary (i.c.) administration of acetylcholine (Ach) in cardiac transplant patients and has been related to early endothelial disfunction; the clinical correlates of this response are still unknown. We infused graded i.c. concentrations of Ach in 32 pts with angiographically smooth coronary arteries 1 to 3 years after heart transplantation. Changes in diameters of the proximal and middle segments of the left anterior descending coronary artery were measured by quantitative coronary angiography (automatic edge detection). The response to Ach ranged from +44% to -58%; at linear regression analysis it was significantly related to the plasma levels of cyclosporine (r = -0.39, p < .05) and triglycerides (r = -0.42, p < .02) but not to vessel diameter, recipient and donor age, time after transplantation, hypertension, cholesterol levels, number of acute rejection episodes and previous cytomegalovirus infections. In heart transplant pts with angiographically normal coronary arteries i.c. Ach may reveal endothelial disfunction which is associated with high cyclosporine and triglycerides plasma levels. Whether this response may predict an earlier development of coronary disease remains to be elucidated.


Strain variation in early innate cytokine induction by Plasmodium falciparum.
Previous work has shown that human donors vary in the magnitude and pattern of cytokines induced when peripheral blood mononuclear cells (PBMCs) are co-cultured with Plasmodium falciparum-infected erythrocytes. Whether P. falciparum strains vary in their ability to induce cytokines has not been studied in detail and is an important question, because variation in cytokine induction could affect parasite virulence and patterns of clinical disease. We investigated the early inflammatory cytokine response to four P. falciparum laboratory strains and five field isolates. Initial studies showed that parasite strain, parasitaemia and PBMC donor all had significant effects on the magnitude of pro-inflammatory cytokine responses (IFN-gamma, GM-CSF, IL-1 beta, TNF-alpha, IL-6, P < 0.005 in all cases). However, we noticed that the most highly inducing parasite strain consistently reached schizont rupture more rapidly than the other strains. When timing of schizont rupture was taken into account, parasite strains no longer differed in their cytokine induction (P = 0.383), although donor effects remained significant (P < 0.001). These data do not support the hypothesis that P. falciparum strains vary in induction of early innate cytokine responses from PBMCs, and instead are consistent with the suggestion that conserved parasite products such as haemozoin or GPI-anchors are the parasite-derived stimuli for cytokine induction.


Transition state theory: variational formulation, dynamical corrections, and error estimates.
Transition state theory (TST) is revisited, as well as evolutions upon TST such as variational TST in which the TST dividing surface is optimized so as to minimize the rate of recrossing through this surface and methods which aim at computing dynamical corrections to the TST transition rate constant. The theory is discussed from an original viewpoint. It is shown how to compute exactly the mean frequency of transition between two predefined sets which either partition phase space (as in TST) or are taken to be well-separated metastable sets corresponding to long-lived conformation states (as necessary to obtain the actual transition rate constants between these states). Exact and approximate criterions for the optimal TST dividing surface with minimum recrossing rate are derived. Some issues about the definition and meaning of the free energy in the context of TST are also discussed. Finally precise error estimates for the numerical procedure to evaluate the transmission coefficient kappaS of the TST dividing surface are given, and it is shown that the relative error on kappaS scales as 1/square root(kappaS) when kappaS is small. This implies that dynamical corrections to the TST rate constant can be computed efficiently if and only if the TST dividing surface has a transmission coefficient kappaS which is not too small. In particular, the TST dividing surface must be optimized upon (for otherwise kappaS is generally very small), but this may not be sufficient to make the procedure numerically efficient (because the optimal dividing surface has maximum kappaS, but this coefficient may still be very small).


Polyphenol-Rich Leaf of Annona squamosa Stimulates Insulin Release from BRIN-BD11 Cells and Isolated Mouse Islets, Reduces (CH2O)n Digestion and Absorption, and Improves Glucose Tolerance and GLP-1 (7-36) Levels in High-Fat-Fed Rats.
Annona squamosa, commonly known as custard apple, is traditionally used for the treatment of various diseases including diabetes, cardiovascular disease (CVD), and gastritis. This study was undertaken to investigate the effects of an ethanolic (80% v/v) extract of A. squamosa (EEAS) leaves in vitro on insulin secretion from clonal pancreatic BRIN BD11 β-cells and mouse islets, including mechanistic studies on the effect of EEAS on membrane potential and intracellular calcium ion concentration. Additional in vitro glucose-lowering actions were assessed. For in vivo studies, high-fat-fed (HFF) obese/normal rats were selected. EEAS increased insulin secretion in vitro in a dose-dependent manner. This effect was linked to β-cell membrane depolarisation and cytoplasmic Ca2+ influx. In the presence of isobutyl methylxanthine (IBMX), tolbutamide, or KCl, the insulin-releasing effect of EEAS was increased, suggesting its effect was also mediated via a KATP-independent pathways. EEAS inhibited insulin glycation, glucose absorption, and DPP-IV enzyme activity in vitro and enhanced glucose uptake and insulin action in 3T3L1 cells. In vivo, gut motility, food intake, glucose tolerance, plasma insulin, and active GLP-1 (7-36) levels were improved, whereas plasma DPP-IV levels were reduced in HFF rats. EEAS attenuated the absorption of sucrose and glucose as well as decreased serum glucose levels after sucrose loading and in situ intestinal perfusion in non-diabetic rats. Rutin, proanthocyanidin, and squafosacin G were putatively identified as the anti-hyperglycaemic phytomolecules in EEAS using HPLC followed by LC-MS analysis. This study illustrates the potential of A. squamosa and its phytoconstituents as a source of potential antidiabetic agents.


The mechanical response of human liver and its relation to histology: an in vivo study.
The mechanical response of human liver is characterized in vivo by means of intra-operative aspiration experiments. Mechanical characterization is combined with histological evaluation of liver tissue biopsies obtained from the resected liver at the site of mechanical testing. This procedure enables a quantitative analysis of the correlation between mechanical response and tissue micro-structure of normal and diseased liver. Ten organs were tested in vivo at multiple locations, as well as ex vivo immediately after resection. Biopsies were analyzed in terms of pathology and percentage of connective tissue content. The change of the mechanical parameters from in vivo to ex vivo has been determined, with an increase of 17% of the proposed stiffness index. The relationship between mechanical parameters and various pathologic conditions affecting the tissue samples has been quantified, with fibrosis leading to a response up to three times stiffer as compared with normal tissue. Increased stiffness can be detected by digital palpation (increased "consistency") and may suggest the presence of a tumor. The present observations suggest that stiffness increase cannot be attributed to the tumoral tissue itself, but rather to the fibrotic stroma that often arise within or adjacent to the tumor. Variation of the mechanical parameters as a function of connective tissue content has been evaluated based on the histological examinations and the results confirm a direct proportionality between stiffness index and connective tissue percentage. The approach described here might eventually lead to a diagnostic procedure and complement other clinical methods, like palpation and ultrasound examination of the liver.