JNK1 is essential for CD8+ T cell-mediated tumor immune surveillance.
JNK1 has divergent roles in regulating the effector functions of CD4+ and CD8+ T cells. However, the function of JNK1 in tumor immune surveillance is unknown. In this study, we show that similar to IFN-gamma-/- mice, JNK1-/- mice are highly susceptible to tumor development after inoculation of both melanoma cell line B16 and lymphoma cell line EL-4. Using T cell depletion and reconstitution approaches, we show that CD8+ T cells, but not CD4+ T cells, from JNK1-/- mice are responsible for tumor susceptibility. JNK1-/- CD8+ T cells have an intrinsic defect in early IFN-gamma gene transcription and production after activation by either anti-CD3/anti-CD28 Abs or dendritic cells loaded with specific Ag in vitro. The impaired IFN-gamma production in JNK1-/- CD8+ T cells is associated with reduced expression of both T-bet and Eomesodermin, indicating that JNK1 regulates the transcription program of CD8+ T cells. Finally, JNK1-/- CD8+ T cells showed reduced perforin expression and impaired CTL function. Taken together, our results demonstrate that JNK1 plays an important role in tumor immune surveillance through regulating the effector functions of CD8+ T cells.


Delivering wound management in a social setting.
As a District Nursing Sister based at a small village surgery, this is a personal account of the author's experiences introducing a new approach for delivering holistic wound management to patients. It deals with the practical and emotional challenges of overcoming barriers to change and forging new working relationships, both within the nursing team and with the patients and wider community. With the encouragement and support of Ellie Lindsay, originator of the Lindsay Leg Club model, Combs Ford Leg Club was set up in 2000 to provide leg ulcer management in an empowered and stigma-free environment. Through the commitment and efforts of nurses, volunteers and patients working together, difficulties and resistance have been confronted and overcome, and Combs Ford Leg Club today is a thriving and vibrant resource, treating, supporting and educating those experiencing leg ulcers or other leg related conditions.


Insertion/deletion polymorphism of the angiotensin-converting enzyme gene and loss of the insertion allele in aldosterone-producing adenoma.
The genetic mechanisms responsible for the formation of adrenocortical adenomas which autonomously produce aldosterone are largely unknown. The adrenal renin-angiotensin system has been implicated in the pathophysiology of these tumours. Angiotensin-converting enzyme (ACE) catalyses the generation of angiotensin II, and the insertion/deletion (I/D) polymorphism of the ACE gene regulates up to 50% of plasma and cellular ACE variability in humans. We therefore examined the genotypic and allelic frequency distributions of the ACE gene I/D polymorphism in 55 patients with aldosterone-producing adenoma, APA, (angiotensin-unresponsive APA n = 28, angiotensin-responsive APA n = 27), and 80 control subjects with no family history of hypertension. We also compared the ACE gene I/D polymorphism allelic pattern in matched tumour and peripheral blood DNA in the 55 patients with APA. The frequency of the D allele was 0.518 and 0.512 and the I allele was 0.482 and 0.488 in the APA and control subjects respectively. Genotypic and allelic frequency analysis found no significant differences between the groups. Examination of the matched tumour and peripheral blood DNA samples revealed the loss of the insertion allele in four of the 25 patients who were heterozygous for the ACE I/D genotype. The I/D polymorphism of the ACE gene does not appear to contribute to the biochemical and phenotypic characteristic of APA, however, the deletion of the insertion allele of the ACE gene I/D polymorphism in 16% of aldosterone-producing adenomas may represent the loss of a tumour suppressor gene/s or other genes on chromosome 17q which may contribute to tumorigenesis in APA.


Increased levels of soluble P-selectin correlate with iron overload in sickle cell disease.
Homozygous sickle cell disease (SCD) is characterised by increased soluble P-selectin (sP-selectin), suggesting increased platelet activation, and high non-transferrin-bound iron (NTBI), reflecting iron overload, possibly due to blood transfusion. Hypothesising a relationship between these processes, we measured both markers in 40 SCD patients and 40 age/gender/race-matched controls, finding increased levels of each marker in the patients (both P<0.001), but more pertinently a significant NTBI/sP-selectin correlation (r=0.52, P<0.001). Both indices were increased in the blood of 15 recently-transfused patients compared with 25 three-month transfusion-free patients (P<0.001), but only sP-selectin was higher in present sickle crisis (P<0.001). We suggest that increased NTBI associated with blood transfusion iron overload in SCD may promote platelet activation.


Renovascular hypertension.
Renovascular disease, particularly when associated with atherosclerosis, is a common cofactor in accelerating hypertension and deteriorating renal function. With increased longevity and effective antihypertensive medications, the prevalence of vascular lesions affecting renal viability is increasing, possibly accounting for 15% of end-stage renal disease. Renal vascular lesions alter renin release and multiple associated mechanisms related to adrenergic and vascular regulation. Several new diagnostic modalities, including captopril renography, duplex ultrasonography, and magnetic resonance angiography, are being applied for noninvasive diagnosis. Advances in interventional radiologic procedures, including endovascular stents and surgical revascularization, offer the potential for both improved blood pressure management and salvage of renal function. Optimal management of renovascular disease depends on careful assessment of the progression of each patient and associated risk of intervention.


Clinical outcomes of mild hyperthermia for locally advanced rectal cancer treated with preoperative radiochemotherapy.
The aim of this report was to determine the impact of hyperthermia (HT) on preoperative radiochemotherapy for locally advanced rectal cancer. Between 1996 and 2007, 235 patients with locally advanced rectal cancer were treated with concurrent preoperative radiochemotherapy with or without HT. The total dose of radiotherapy was 39.6 Gy for 109 patients (group A) and 45 Gy for 126 patients (group B). Two or three cycles of chemotherapy were administered. Hyperthermia was given immediately after radiotherapy. In the HT subgroup of group A, more patients achieved down-staging of T stage when compared to the non-HT subgroup (57.9% versus 38%, p = 0.047). For the cN+ subgroup of all patients, the number of patients with ypN+ were significantly less in the HT subgroup (25% versus 50%, p = 0.022). In group A, HT appeared to reduce distant metastasis, increase disease-free survival, and improve overall survival. HT seemed to increase the response of both primary tumour and lymph nodes to preoperative radiochemotherapy in patients with locally advanced rectal cancer. The relationship between increased response by HT and survival should be confirmed by a large prospective randomised trial.


Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway.
The major drug binding site of sodium channels is inaccessible from the extracellular side, drug molecules can only access it either from the membrane phase, or from the intracellular aqueous phase. For this reason, ligand-membrane interactions are as important determinants of inhibitor properties, as ligand-protein interactions. One-way to probe this is to modify the pH of the extracellular fluid, which alters the ratio of charged vs. uncharged forms of some compounds, thereby changing their interaction with the membrane. In this electrophysiology study we used three different pH values: 6.0, 7.3, and 8.6 to test the significance of the protonation-deprotonation equilibrium in drug access and affinity. We investigated drugs of several different indications: carbamazepine, lamotrigine, phenytoin, lidocaine, bupivacaine, mexiletine, flecainide, ranolazine, riluzole, memantine, ritanserin, tolperisone, silperisone, ambroxol, haloperidol, chlorpromazine, clozapine, fluoxetine, sertraline, paroxetine, amitriptyline, imipramine, desipramine, maprotiline, nisoxetine, mianserin, mirtazapine, venlafaxine, nefazodone, and trazodone. We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics. As expected, we observed a strong correlation between the acidic dissociation constant (pKa) of drugs and the pH-dependence of their potency. Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation. Our data are best explained by a model where drug molecules can be trapped in at least two chemically different environments: A hydrophilic trap (which may be the aqueous cavity within the inner vestibule), which favors polar and less lipophilic compounds, and a lipophilic trap (which may be the membrane phase itself, and/or lipophilic binding sites on the channel). Rescue from the hydrophilic and lipophilic traps can be promoted by alkalic and acidic extracellular pH, respectively.


Therapeutic misalliances.
This paper explores aspects of the psychopathology of the patient-therapist relationship, and specifically defines and illustrates the concept of therapeutic misalliances. After a review of the relevant literature, two extended clinical vignettes are presented in order to explore efforts by both patient and therapist to create and modify conscious and unconscious misalliances. A tentative effort is made to delineate attempts on the part of the patient to "cure" his therapist of countertransference difficulties that have contributed to a therapeutic misalliance. Such efforts are based on the patient's extensive unconscious perceptions of his therapist's difficulties and these are documented in detail. In discussing this clinical material, the following are considered: The means of recognizing therapeutic misalliances from the therapist's subjective awareness and from the patient's associations; the interfering and therapeutically helpful aspects of the creation and analytic resolution of misalliances; the techniques through which therapeutic misalliances may be modified; the motives in both the patient and therapist or analyst that prompt the creation of misalliances; the curative aspects of the patient's positive introjective identification with the therapist and the damaging aspects of incorporative identifications with a therapist who is in difficulty; the importance of the adaptational-interactional framework in understanding the patient-therapist and patient-analyst relationships; and the importance of the therapist's personality and behavior, in addition to his role in providing the patient with well-timed and meaningful interpretive interventions.


Rap1A, Rap1B, and β-Adrenergic Signaling in Autologous HCT: A Randomized Controlled Trial of Propranolol.
Successful hematopoietic cell transplantation (HCT) depends on rapid engraftment of the progenitor and stem cells that will reestablish hematopoiesis. Rap1A and Rap1B are two closely related small GTPases that may affect platelet and neutrophil engraftment during HCT through their roles in cell adhesion and migration. β-adrenergic signaling may regulate the participation of Rap1A and Rap1B in engraftment through their inhibition or activation. We conducted a correlative study of a randomized controlled trial evaluating the effects of the nonselective β-antagonist propranolol on expression and prenylation of Rap1A and Rap1B during neutrophil and platelet engraftment in 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for 1 week prior to and 4 weeks following HCT. Blood was collected 7 days (baseline) and 2 days (Day -2) before HCT, and 28 days after HCT (Day +28). Circulating polymorphonuclear cells (PMNC) were isolated and analyzed via immunoblotting to determine levels of prenylated and total Rap1A versus Rap1B. Twelve participants were randomized to the intervention and 13 to the control. Rap1A expression significantly correlated with Rap1B expression. Rap1B expression significantly correlated with slower platelet engraftment; however, this association was not observed in the propranolol-treated group. There were no significant associations between neutrophil engraftment and Rap1A or Rap1B expression. Post hoc exploratory analyses did not reveal an association between social health variables and Rap1A or Rap1B expression. This study identifies a greater regulatory role for Rap1B than Rap1A in platelet engraftment and suggests a possible role for β-adrenergic signaling in modulating Rap1B function during HCT.


Role of thermal diffusion in cw IR laser absorption in gas mixtures.
The absorption of radiation from a cw CO(2) laser by a mixture of absorbing SF(6) and transparent buffer gases has been measured as a function of pressure of added transparent gas (C(4)H(10)). The results are analyzed in terms of thermal diffusion of excited SF6 molecules out of the irradiation zone. In the 60-400-Torr pressure range, thermal difusion depletes the concentration of SF(6) so that the overall absorption is decreased and competes with the various channels of collisional relaxation which enhance absorption. An approximate semiempirical expression is used to determine the transient perturbation of concentration which occurs inside the laser beam.


Robert Spitzer and psychiatric classification: technical challenges and ethical dilemmas.
Dr Robert Leopold Spitzer (May 22, 1932-December 25, 2015), the architect of modern psychiatric diagnostic criteria and classification, died recently at the age of 83 in Seattle. Under his leadership, the American Psychiatric Association's (APA) Diagnostic and Statistical Manuals (DSM) became the international standard.


Can genetic material retrotransposition be a cause of pathology accompanying cerebral aneurysm rupture?
Our considerations were prompted by observation of patients who underwent surgery due to cerebral aneurysm rupture. Elevated anti-HIV antibody titers were detected in such patients. The above condition was not observed either in subjects with intracranial hemorrhages from cerebral angiomas. The observed titers remained certainly below the cut off level indicating contact with HIV. We analyzed the subpopulations of peripheral blood lymphocytes both in the surgery patients and in the control group represented by blood collected from blood donors. On the other hand, the proliferation potential of circulating lymphocytes in the blood of patients with subarachnoid hemorrhages due to cranial aneurysm ruptures was found to be decreased. Dislocation of transposons, so-called 'unauthorized recombination' is known to occur within the framework of genetic code pathology. Endogenous human viruses have been described, and they may be involved in the development of autoimmune disorders. Additionally, viruses involved in autoimmune processes, which may be 'identical' with retrotransposons, have been described. Moreover, there are studies demonstrating that AIDS is caused by retrotransposition of genetic code material fragments. Our considerations are substantiated by ultrastructural analyses of material coming from the gyrus rectus cortex fragments, resected in patients who underwent clipping of a ruptured aneurysm of the anterior communicating artery. We demonstrated in neuronal chromatin the presence of a molecule ca. 80 nm in diameter, corresponding with its size to retroviruses or genetic material molecules with altered substructure. The authors suggest a new mechanism of development of neurological deficits in patients with ruptured cerebral aneurysms.


Perceptions of physiotherapists about their role in health promotion at an acute hospital: a qualitative study.
To investigate the perceptions of physiotherapists about their role in health promotion in an acute inpatient setting. Qualitative design using focus groups within a constructivist framework. Focus groups were recorded, transcribed verbatim and analysed using a constant comparative method. An acute National Health Service (NHS) hospital trust. Three focus groups were conducted with a total of 22 physiotherapists who were recruited purposively from the medical and surgical unit of the study hospital. Participants generally perceived health promotion to be within their scope of practice, particularly in relation to the promotion of physical activity and smoking cessation. Whilst some facilitators to engaging in health promotion were discussed, a large number of barriers to routine engagement in health promotion were identified. These included time constraints, the focus of acute settings on discharge, and scepticism of effectiveness. Pre- and postregistration physiotherapy education as well as mandatory training in NHS trusts should be reviewed to equip the workforce to engage in this crucial area of health care.


Two-dimensional thin-layer chromatographic method for the analysis of ochratoxin A in green coffee.
A low-cost thin-layer chromatographic method has been developed for the presumptive measurement of ochratoxin A (OTA) at 5 microg/kg in green coffee beans. The analytical method consisted of extracting OTA by shaking the beans with a mixture of methanol and aqueous sodium bicarbonate solution, which was then purified by liquid-liquid partition into toluene. OTA was separated by normal-phase two-dimensional thin-layer chromatography and detected by visual estimation of fluorescence intensity under a UV lamp at 365 nm. The chromatography solvents were toluene-methanol-formic acid (8:2:0.03) for the first development and petroleum ether-ethyl acetate-formic acid (8:10:1) for the second dimension development. This method was tested with uncontaminated green coffee bean samples spiked with an OTA standard at four different concentrations (5, 10, 20, and 30 microg/kg). The method is rapid, simple, and very easy to implement in coffee-producing countries. It is highly selective and does not involve the use of chlorinated solvents in the sample extraction step. This inexpensive method has been applied to different types of green coffee samples from various countries (Zimbabwe, Brazil, India, Uganda, Colombia, and Indonesia) and different manufacturers, and no OTA below the detection limit of 5 microg/kg was detected in any samples analyzed.


Hedgehog inhibitors with and without adjunctive therapy in treatment of locally advanced basal cell carcinoma.
Hedgehog inhibitor therapy (HHIT) is considered first-line treatment for locally advanced, unresectable basal cell carcinoma (laBCC). HHIT often results in a partial response, which requires adjunctive therapy (AT) post HHIT. We present real-world data for laBCCs undergoing HHIT ± AT. Retrospective review at Duke University from 11/01/2007 through 5/20/2020 revealed 13 patients treated with systemic HHIT (sonidegib or vismodegib) for laBCC. Fourteen laBCCs were identified in 13 patients. LaBCCs were treated with sonidegib (n = 10, 71%) or vismodegib (n = 4, 29%) for a median (IQR) of 9.4 (9.3) or 9.8 (8.5) months, respectively. The median (IQR) follow-up time from HHIT initiation was 15.5 (8.7) months. Tumors were most often located on the trunk (43%), followed by head and neck (29%), extremities (21%), and orbit/periorbital area (7%). Nine laBCCs (64%) were treated with HHIT alone, of which five (36%) achieved complete response (CR), four (29%) achieved partial response (PR), and five (36%) achieved CR with combined HHIT and AT post-HHIT. Duration of HHIT treatment (IQR) was 7.5 (3.5) months in the 10 CR patients, versus 15.1 (6.3) months in the four PR patients (P = 0.024). Nine patients (69%) experienced adverse events from HHIT, most commonly ageusia/dysgeusia, muscle spasms, and alopecia. As a single institutional experience, we report 10/14 laBCCs (71%) with CRs without recurrence and 4/14 laBCCs (29%) with PRs with HHIT ± AT over median follow-up of 15.5 months. Longer follow-up and larger cohorts evaluating responses with HHIT followed by AT are needed to substantiate our findings.


Traumatic injuries caused by hazing practices.
Hazing is defined as committing acts against an individual or forcing an individual into committing an act that creates a risk for harm in order for the individual to be initiated into or affiliated with an organization. Hazing is an enduring activity with roots that date back to the ancient and medieval eras. It has become increasingly prevalent in fraternities and sororities, high school and college athletic organizations, the military, professional sports teams, and street gangs. Scant information is available in the medical literature regarding hazing. This article reviews the history of hazing, provides statistics regarding its prevalence, presents information on specific hazing practices and consequent traumatic injuries, and assesses alcohol's influence on hazing. It also offers recommendations on how to recognize victims of hazing in the Emergency Department and proposes guidelines for their treatment. Current legislation and information on the prevention of traumatic injuries from hazing are discussed.


Connexin 26 expression correlates with less aggressive phenotype of intestinal type-gastric carcinomas.
Connexin 26 (Cx26), one of the gap junction-forming family members, is more controversial than other members, as a tumor suppressor. Here, we assessed Cx26 expression in gastric carcinoma, which has not been investigated before, and its clinical significance including survival analyses. Cx26 expression was assessed in 205 tissue samples from gastric carcinoma by immunohistochemistry. Of 205 gastric carcinoma cases, 79 (38.5%) were positive for Cx26 with mainly cytoplasmic localization compared to sporadic membranous staining in normal epithelium, and the expression levels were confirmed by Western blotting and real-time PCR. Negative associations were revealed between Cx26 expression and most clinicopathologic features (all P<0.05). Notably, high Cx26 expression was associated with histological intestinal-type (P=0.017) and early stage of gastric carcinoma. The multivariate regression analysis revealed that positive Cx26 expression was an independent prognostic predictor of intestinal-type GC (P=0.023, HR=2.019). Our findings suggest that aberrant expression of Cx26 in cytoplasm plays a tumor-suppressor role in gastric carcinoma and is an independent biomarker for favorable prognosis in intestinal-type gastric carcinoma.


Impairment of retinal adaptive circuitry in the myopic eye.
Previous studies have proposed that the inner retina is affected in myopes. This study aimed to investigate the changes in adaptive circuitry of the inner retina in myopia, using the global flash multifocal electroretinogram (global flash mfERG) with different levels of contrast (luminance modulation). Fifty-four myopes had global flash mfERG recorded with different contrasts. The direct component (DC) and the induced component (IC) of the mfERG response were pooled into six regions for analysis. The response amplitudes and implicit times at different contrasts were also analysed. Results showed that myopes had significant reduction in the paracentral DC amplitude for the 29% and 49% contrasts and in the paracentral IC amplitude at all contrasts measured. The peripheral IC amplitude for the 49% contrast was also reduced. No significant change was found in implicit time for either DC or IC response. Refractive error explained about 14% of the variance in DC and 16% of the variance in IC amplitude respectively; axial length could not account for additional variance in either paracentral DC or IC amplitudes in the hierarchical regression models used. We concluded that the paracentral retinal region in myopes showed signs of impaired retinal adaptation, suggesting a functional loss at the inner retinal layer. In addition, functions attributed to the outer retinal layer showed only small changes due to myopia.


Purine-related metabolites and their converting enzymes are altered in frontal, parietal and temporal cortex at early stages of Alzheimer's disease pathology.
Adenosine, hypoxanthine, xanthine, guanosine and inosine levels were assessed by HPLC, and the activity of related enzymes 5'-nucleotidase (5'-NT), adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) measured in frontal (FC), parietal (PC) and temporal (TC) cortices at different stages of disease progression in Alzheimer's disease (AD) and in age-matched controls. Significantly decreased levels of adenosine, guanosine, hypoxanthine and xanthine, and apparently less inosine, are found in FC from the early stages of AD; PC and TC show an opposing pattern, as adenosine, guanosine and inosine are significantly increased at least at determinate stages of AD whereas hypoxanthine and xanthine levels remain unaltered. 5'-NT is reduced in membranes and cytosol in FC mainly at early stages but not in PC, and only at advanced stages in cytosol in TC. ADA activity is decreased in AD when considered as a whole but increased at early stages in TC. Finally, PNP activity is increased only in TC at early stages. Purine metabolism alterations occur at early stages of AD independently of neurofibrillary tangles and β-amyloid plaques. Alterations are stage dependent and region dependent, the latter showing opposite patterns in FC compared with PC and TC. Adenosine is the most affected of the assessed purines.


The management of bilateral ureteric injury following radical hysterectomy.
Iatrogenic ureteric injury is a well-recognised complication of radical hysterectomy. Bilateral ureteric injuries are rare, but do pose a considerable reconstructive challenge. We searched a prospectively acquired departmental database of ureteric injuries to identify patients with bilateral ureteric injury following radical hysterectomy. Five patients suffered bilateral ureteric injury over a 6-year period. Initial placement of ureteric stents was attempted in all patients. Stents were placed retrogradely into 6 ureters and antegradely into 2 ureters. In 1 patient ureteric stents could not be placed and they underwent primary ureteric reimplantation. In the 4 patients in which stents were placed, 2 were managed with stents alone, 1 required ureteric reimplantation for a persistent ureterovaginal fistula, and 1 developed a recurrent stricture. No patient managed by ureteric stenting suffered deterioration in serum creatinine. We feel that ureteric stenting, when possible, offers a safe primary management of bilateral ureteric injury at radical hysterectomy.


[A case of Crohn's disease following an infection by Epstein-Barr virus].
Infection by the Epstein-Barr virus (EBV) has been linked to the development of autoimmune diseases and recent studies have investigated its specific influence on inflammatory bowel diseases. This is a case report of a 20 year old patient who was diagnosed with Crohn's disease following a prolonged manifestation of infectious mononucleosis. The current information regarding the association between EBV and the development of inflammatory bowel diseases is discussed.


[Laryngeal and hypopharyngeal carcinoma--the patient's perspective].
Carcinoma of the larynx and hypopharynx are the most often head and neck malignancies. The make diagnosis of the disease early and established the best methods of treatment for individual patients is important just the same as a good relation between doctor and patient. The subject of the study has been patient's judgements about quality of diagnosis, treatment and follow-up procedures. 60 patients (10 women and 50 men) has been inquired with contents the same list of questions. All patients have been treated because of carcinoma of the larynx and laryngopharynx during last 5 years in the Department of Otolaryngology Medical Academy in Warsaw. The authors analysed all answers for questions. The general conclusions have been definite: the patient's knowledge about laryngeal and pharyngeal anatomy and functions is minimal, also they know not much about neoplasm disease and cigarettes and alcohol harmfulness. The patient's opinion at doctor's professional authority was good. It seems to be necessary to do much more to improve people health education especially wholesome behaviour.


Copper(I) complexes with bipyridyl and phosphine ligands: a systematic study.
Phosphorescent copper(I) complexes carrying 2,2'-bipyridyl derivatives and phosphine ligands have been prepared and fully characterised. The role of the bipyridyl as well as the phosphine ligands in defining the optical, as well as the chemical properties of the complexes, are discussed. The light emission of these complexes is investigated as a function of the molecular geometry: rigid complexes with restricted freedom to rearrange in the excited state are found to show a quantum yield of phosphorescence one order of magnitude higher than those complexes with no steric constraint. The complexes have been extruded in a polymer matrix as a proof of principle of their processability.


Inhibition by certain plant extracts of the binding and adenylate cyclase stimulatory effect of bovine thyrotropin in human thyroid membranes.
The present studies were undertaken to explore the mechanism by which, as previous studies have shown, freeze-dried aqueous extracts (FDE) of plants of the species Lycopus virginicus and Lycopus europaeus, Melissa officinalis (Laminaceae), and Lithospermum officinale (Boraginaceae) have the ability to inhibit at least many of the effects of exogenous and endogenous TSH on the thyroid gland. To this end, we have examined the in vitro effects of FDE from these plants on the ability of bovine TSH (bTSH) to both bind to human thyroid plasma membranes (TPM) and activate adenylate cyclase therein. FDE of these four species produced a dose-related, ultimately complete, inhibition of the binding of 125I-labeled bTSH when studied at 4 C in a 20 mM Tris-HCl-0.5% BSA buffer, pH 7.45. Half-maximum inhibition of bTSH binding was produced by approximately 50 mU/ml bTSH and only about 10-30 micrograms/ml of the four active FDE. When studied in Tris-BSA-50 mM NaCl buffer at 37 C, these FDE remained inhibitory to bTSH binding, but their potency was decreased to about one fifth of that seen in the absence of NaCl. The binding of [125I]hCG to rat testis membranes was also inhibited by all of these FDE, but no effect on the binding of [125I]insulin to crude rat liver membranes was observed. In concentrations as high as 1 mg/ml, FDE of Verbena officinalis (Verbenaceae), which belongs to the same order (Tubiflorae) as the other plants, but exhibits no antithyrotropic or antigonadotropic activity in vivo, had no effect on either the binding of bTSH to thyroid membranes or the binding of hCG to rat testis membranes. No inhibition of [125I]bTSH binding occurred when TPM were preincubated with the four active FDE, washed, and then incubated with [125I]bTSH in medium devoid of FDE. Hence, the inhibition of [125I]bTSH binding seen when labeled hormone and active FDE were added together was not due to irreversible binding of FDE to TPM or damage to the TSH receptor. When [125I]bTSH was incubated with the active FDE in Tris-BSA and the mixture was chromatographed on Sephadex G-100 using the same buffer, [125I]bTSH was shifted from an apparent mol wt of 30,000 and eluted at the void volume. Direct binding of [125I]bTSH in fractions from the new, large molecular peak was nil. Addition of a large excess of unlabeled bTSH during preincubation prevented the shift in the elution pattern of [125I] bTSH produced by these FDE.(ABSTRACT TRUNCATED AT 400 WORDS)


[MELATONIN: THE POSSIBILITY TO ANALYSE THE MARKER OF AGE-RELATED PATHOLOGY IN THE BUCCAL EPITHELIUM AND URINE].
Extrapineal and pineal melatonin is the marker of the aging rate of organism making it possible to characterize functional condition of the neuro-immuno-endocrine system. In this article we have used the new method for non-invasive diagnostics of melatonin expression in buccal epithelium and determination of the main melatonin metabolite 6-hydroxymelatonin sulfate (6-HMS) in urine of elderly people. Normal, impaired and enhanced melatonin expression was documented in 20.5%, 43.2% and 36.30% of the patients respectively. Such comprehensive melatonin and 6-COMT studies can be recommended for elderly patients with oncological, neurodegenerative, cardiovascular diseases, and ageing macular dystrophy. Moreover, melatonin expression analysis in buccal cells can be used for integral investigation of biorhythms in elderly people.


Control-value theory in the context of teaching: does teaching quality moderate relations between academic self-concept and achievement emotions?
Students' self-concept of ability is an important predictor of their achievement emotions. However, little is known about how learning environments affect these interrelations. Referring to Pekrun's control-value theory, this study investigated whether teacher-reported teaching quality at the classroom level would moderate the relation between student-level mathematics self-concept at the beginning of the school year and students' achievement emotions at the middle of the school year. Data of 807 ninth and tenth graders (53.4% girls) and their mathematics teachers (58.1% male) were analysed. Students and teachers completed questionnaires at the beginning of the school year and at the middle of the school year. Multi-level modelling and cross-level interaction analyses were used to examine the longitudinal relations between self-concept, teacher-perceived teaching quality, and achievement emotions as well as potential interaction effects. Mathematics self-concept significantly and positively related to enjoyment in mathematics and negatively related to anxiety. Teacher-reported structuredness decreased students' anxiety. Mathematics self-concept only had a significant and positive effect on students' enjoyment at high levels of teacher-reported cognitive activation and at high levels of structuredness. High teaching quality can be seen as a resource that strengthens the positive relations between academic self-concept and positive achievement emotions.


Fanconi anemia D2 protein confers chemoresistance in response to the anticancer agent, irofulven.
The Fanconi anemia-BRCA pathway of genes are frequently mutated or epigenetically repressed in human cancer. The proteins of this pathway play pivotal roles in DNA damage signaling and repair. Irofulven is one of a new class of anticancer agents that are analogues of mushroom-derived illudin toxins. Preclinical studies and clinical trials have shown that irofulven is effective against several tumor cell types. The exact nature of irofulven-induced DNA damage is not completely understood. Previously, we have shown that irofulven activates ATM and its targets, NBS1, SMC1, CHK2, and p53. In this study, we hypothesize that irofulven induces DNA double-strand breaks and FANCD2 may play an important role in modulating cellular responses and chemosensitivity in response to irofulven treatment. By using cells that are proficient or deficient for FANCD2, ATR, or ATM, we showed that irofulven induces FANCD2 monoubiquitination and nuclear foci formation. ATR is important in mediating irofulven-induced FANCD2 monoubiquitination. Furthermore, we showed that FANCD2 plays a critical role in maintaining chromosome integrity and modulating chemosensitivity in response to irofulven-induced DNA damage. Therefore, this study suggests that it might be clinically significant to target irofulven therapy to cancers defective for proteins of the Fanconi anemia-BRCA pathway.


[A developmental history of endoscopy].
The real development of endoscopy began from modern times, though people have attempted to observed cavities of human body for advancing their knowledge of diseases for a long time. Generally, the development of endoscopy can be divided into the following stages: the stage of rigid - tube system, semiflexible instruments, fiberoptic endoscopy, endoscopic ultrasonography and electronic endoscopy etc. Now, endoscopy is not only used in diagnosis, but also in therapy. The development of endoscopy started quite late in China. However, due to the great efforts made by the endoscopic physicians and some experts, the clinical applications and operations of endoscopy have been upgraded to the international level, and the manufacture engineers of medical instruments have also made contributions to the endoscopic development of China.


Genetic characterization of JC virus Tokyo-1 strain, a variant oncogenic in rodents.
The genome DNA of JC virus Tokyo-1 strain [JCV(Tokyo-1)], a variant oncogenic in rodents, was molecularly cloned directly from the brain of a Japanese patient with progressive multifocal leukoencephalopathy and from tissue culture, and the restriction enzyme cleavage pattern and regulatory sequences were determined. The restriction pattern of the cloned JCV(Tokyo-1) DNA was different from those of JCVs previously reported in the United States and Germany. Also, the arrangement of the regulatory sequence was unique to this strain. Thus JCV(Tokyo-1) can be classified as a new subtype. The relationship between the restriction pattern and the regulatory sequence of JCV(Tokyo-1), and its characteristic oncogenicity, is discussed.


Luteinizing hormone release after administration of the gonadotropin-releasing hormone agonist Fertilan (goserelin) for synchronization of ovulation in pigs.
The generic GnRH agonist, Fertilan (goserelin), was tested for the ability to induce an LH surge and ovulation in estrus-synchronized gilts. Three experiments were performed to 1) examine the effect of various doses of Fertilan on secretion of LH in barrows, to select doses to investigate in gilts (Exp. 1); 2) determine doses of Fertilan that would induce a preovulatory-like rise of LH in gilts (Exp. 2); and 3) determine the time of ovulation after Fertilan treatment (Exp. 3). In Exp. 1, 10 barrows were injected on d 1, 4, 7, 10, and 13 with 10, 20, or 40 microg of Fertilan; 50 microg of Gonavet (depherelin; GnRH control) or saline (negative control); and sequential blood samples were collected for 480 min. There was a dose-dependent stimulation (P < 0.05) of LH release. Maximal plasma concentrations of LH (LH(MAX)) were 2.1 +/- 0.2, 4.1 +/- 0.3, 2.6 +/- 0.4, and 3.4 +/- 0.3 ng/mL after 10, 20, and 40 microg of Fertilan and 50 microg of Gonavet, respectively, and duration of release was 78 +/- 9, 177 +/- 12, 138 +/- 7, and 180 +/- 11 min, respectively. Fertilan doses of 10 and 20 microg were deemed to be the most suitable for testing in gilts. In Exp. 2, 12 gilts received (after estrus synchronization with Regumate and eCG) injections of 10 or 20 microg of Fertilan or 50 microg of Gonavet 80 h after eCG to stimulate a preovulatory-like LH surge and ovulation. An LH surge was induced in 3 of the 4 gilts in both of the Fertilan groups and in all of the Gonavet-treated gilts. Characteristics of induced release of LH did not differ among groups: LH(MAX), 5.0 +/- 0.9 vs. 4.6 +/- 1.8 vs. 6.6 +/- 1.1 ng/mL; duration, 11.7 +/- 2.0 vs. 12.3 +/- 2.2 vs. 14.3 +/- 0.5 h; interval from GnRH injection to LH(MAX), 4.0 +/- 2.0 vs. 6.7 +/- 1.3 vs. 5.8 +/- 1.6 h. In Exp. 3, estrus-synchronized gilts were injected with 20 microg of Fertilan (n = 8) or 50 microg of Gonavet (n = 4), and the time of ovulation was determined by repeated endoscopic examination. Time of ovulation ranged from 34 to 42 h postGnRH; however, ovulation occurred earlier in the Gonavet compared with the other groups (P < 0.05). Results of these experiments indicate that 1) barrows are an appropriate model for determining GnRH doses that can be effective in inducing a preovulatory-like LH surge in females; 2) the generic GnRH agonist Fertilan, at doses of 10 to 20 microg, can stimulate an LH surge in gilts, with subsequent ovulation; and 3) Fertilan at doses of 10 and 20 microg should be examined further for use in fixed-time insemination protocols.


A convergent synthetic approach using sterically demanding aryldipyrrylmethanes for tuning the pocket sizes of cofacial bisporphyrins.
Meso substitution opposite to the spacer provides a convenient approach for tuning the pocket sizes of pillared cofacial bisporphyrins. The synthesis and coordination chemistry of xanthene and dibenzofuran anchored platforms structurally modified with 2,6-dimethoxyaryl groups are described. Comparative structural analysis of xanthene derivatives confirms the ability of the trans-aryl groups to adjust the vertical dimension of the cofacial cleft: 7 (C(97)H(106)Cl(4)N(8)O(5)), monoclinic, space group P2(1)/c, a = 28.8353(12) A, b = 17.1139(7) A, c = 17.5978(7) A, beta = 98.826(1) degrees, Z = 4; 8 (C(101)H(123)Cl(2)N(8)O(11.5)Zn(2)), monoclinic, space group P2(1)/n, a = 14.5517(6) A, b = 22.9226(10) A, c = 28.5155(13) A, beta = 90.312(14) degrees, Z = 4; 12 (C(99)H(102)Cl(14)N(8)O(5)Mn(2)), monoclinic, space group P2/c, a = 19.5891(3) A, b = 15.0741(2) A, c = 33.2019(6) A, beta = 91.947(10) degrees, Z = 4. The convenience and versatility of this synthetic method offers intriguing opportunities to specifically tailor the binding pockets of cofacial bisporphyrins for the study of small-molecule activation within a proton-coupled electron transfer framework.


Effects of connexin-mimetic peptides on perfusion pressure in response to phenylephrine in isolated, perfused rat kidneys.
Gap junction intercellular communication plays a fundamental role in various tissues and organs. Gap junctions transfer ions and molecules between adjacent cells and are formed by connexins (Cx). It is supposed that vascular conducted responses, which most likely spread through gap junctions in vascular beds, regulate microcirculatory blood flow and maintain vascular resistance. This study provides functional evidence supporting the critical role of gap junctions in a physiological setting and in phenylephrine (PE)-induced vasoconstriction using an ex vivo kidney perfusion technique. Using the isolated, perfused kidney model, infusion of gap junction inhibitors and PE, we examined the local effect of gap junction communication. Additionally, gap junction proteins Cx37, Cx40 and Cx43 were detected by immunofluorescence. First, changes in the perfusion pressure were analyzed by infusing the nonselective gap junction uncoupler, 18α-glycyrrhetinic acid (18α-GA), and specific connexin-mimetic peptide inhibitors, (37,43)Gap27, (40)Gap27 and (43)Gap26. Administration of 18α-GA and (43)Gap26 significantly elevated perfusion pressure while infusion of (40)Gap27 and (37,43)Gap27 had no effect. Second, we examined the effect of infusing gap junction inhibitors on PE-induced vasoconstriction. Infusion of 18α-GA and (40)Gap27 significantly suppressed the increase in perfusion pressure induced by PE, while (43)Gap26 and (37,43)Gap27 had no effect. Third, we confirmed by immunofluorescence that Cx37, Cx40 and Cx43 were found in the endothelial cells of interstitial microvessels and that Cx40 was localized in glomerular mesangial cells as well as in smooth muscle cells of the juxtaglomerular area. This study showed that Cx43 plays a pivotal role in regulating renal vascular resistance and that Cx40 attenuates PE-induced vasoconstriction. These results provide new evidence that gap junctions may control renal circulation and vascular responses.


Waning of Influenza Vaccine Protection: Exploring the Trade-offs of Changes in Vaccination Timing Among Older Adults.
In recent studies of influenza vaccine effectiveness (VE), lower effectiveness with increasing time since vaccination was observed, raising the question of optimal vaccination timing. We sought to evaluate the estimated number of influenza-associated hospitalizations among older adults due to potential changes in vaccination timing. Using empirical data and a health state transition model, we estimated change in influenza-associated hospitalizations predicted to occur among the US population aged ≥65 years if vaccination were delayed until October 1. We assumed the vaccination timing, coverage, and effectiveness observed in 2012-2013 as a prototypical influenza season, approximately 7% monthly waning of VE, and that between 0% and 50% of individuals who usually get vaccinated earlier than October failed to get vaccinated. We also assessed change in influenza-associated hospitalizations if vaccination uptake shifted substantially toward August and September. In a typical season, delaying vaccination until October increased influenza hospitalizations if more than 14% of older adults usually vaccinated in August and September failed to get vaccinated. The consequences of delayed vaccination depended heavily on influenza season timing, rate of waning, and overall VE. A shift toward vaccination in August and September led to, on average, an increase in influenza-associated hospitalizations, but this result was also sensitive to influenza season timing. Consequences of delayed vaccination varied widely. Uncertainties about vaccine waning and effects of a delay on vaccine coverage suggest it is premature to change current vaccine recommendations, although it may be prudent to prevent a substantial shift toward early vaccination.


Total skin electron treatment of extensive cutaneous lesions in Kaposi sarcoma.
We report on a 62-year-old HIV-negative male patient with Kaposi sarcoma. After 8 years of treatment of smaller localized skin lesions with surgery and local radiotherapy, the patient developed extensive lesions of the whole skin. The extent of the lesions required the administration of the total skin electron therapy (TSET). Until then, TSET had been used at our Department only for the treatment of mycosis fungoides. The dose delivered was 30 Gy higher than in a conventional radiotherapy treatment, where doses are usually between 8 and 24 Gy. Six months after the TSET therapy, the lesions completely regressed, except for two large facial lesions, which were surgically removed. Major side effects were mild erythema and hyperpigmentation of the skin. Erythema disappeared a month after the therapy.


The role of DNA index as a prognostic factor in early cervical carcinoma.
The value of DNA index as a prognostic factor in early cervical cancers was investigated. A total of 124 patients who underwent radical hysterectomy for stages IB-IA cervical cancers from 1/1982 to 12/1985 were included. Paraffin blocks were available in only 98 patients for the analysis. After dewaxing, rehydrating, and enzyme disaggregation, cells were subjected to dual parameter flow cytometry. Tumor DNA index was calculated and the results were correlated with 5-year survival, stage, grade, tumor size, nodal metastasis, surgical margins, and lymphovascular invasion. There were 1% hypoploid, 7.3% diploid, 72.9% aneuploid, 16.7% tetraploid, and 2.1% hyperploid. At the end of 5 years, there were 69 alive and 27 dead patients with mean DNA indices of 1.50 +/- 0.3 and 1.70 +/- 0.3, respectively. t Test analysis revealed that mean DNA index of deceased patients was significantly higher than that of alive ones (P = 0.008). Survival analysis demonstrated the prognostic significance of DNA index 1.70 (P = 0.017). Median survival of patients with DNA index of 1.70 or greater was 36 months in contrast to 73.5 months for those with DNA index less than 1.70. Multivariate analysis subsequently confirmed DNA index of 1.70 as an independent prognostic indicator with a hazard ratio of 2.05.


Annexin 5 inhibits thyrotropin releasing hormone (TRH) stimulated prolactin release in the primary culture of rat anterior pituitary cells.
Annexin 5, a novel calcium-phospholipid binding protein, is thought to be involved in hormone secretion by the anterior pituitary gland. Gonadotropin releasing hormone stimulates annexin 5 synthesis, which, in turn, enhances gonadotoropin secretion. On the other hand, annexin 5 was shown to inhibit prolactin release in vitro. To understand the nature of the opposing effects of annexin 5 on these two major pituitary hormones, the present study examines the inhibitory effect of annexin 5 on prolactin release in relation to thyrotropin stimulating hormone (TRH) using primary cultures of anterior pituitary cells of adult female rats. While recombinant rat annexin 5 was found to have little effect on basal prolactin release, it significantly inhibited TRH-stimulated prolactin release. Addition of specific anti-annexin 5 serum to the culture increased basal prolactin release in a concentration dependent manner, and no further increase in prolactin release was observed following application of TRH in the presence of anti-annexin 5. The enhanced basal prolactin release induced by anti-annexin 5 was reversed by the simultaneous administration of indomethacin, an inhibitor of cyclooxygenase. These results demonstrate that endogenous pituitary annexin 5 exerts an inhibitory effect on prolactin release and suggest that this is attained by suppression of eicosanoid synthesis in vitro.


Mapping the diversity of gender preferences and sex imbalances in Indonesia in 2010.
Indonesia is usually viewed as a country free of the acute forms of gender discrimination observed elsewhere in East or South Asia, a situation often ascribed to Indonesia's bilateral kinship system. I re-examine this hypothesis by focusing on ethnic and regional variations in sex differentials. New indicators of marriage practices and gender bias derived from 2010 census microdata highlight the presence of patrilocal patterns as well as a distinct presence of son preference in fertility behaviour in many parts of the archipelago. I also present evidence for excessive child sex ratios and excess mortality of females in some areas that appear to be related to son preference and patrilocal residence systems. The findings confirm the association between son preference, sex differentials in mortality, prenatal sex selection, and kinship systems. I conclude with a more regional perspective on demographic vulnerability of females, distinguishing bilateral South East Asia from more patrilineal Melanesia.


Beneficence and the professional's moral imperative.
This article offers a brief discussion of the definition and importance of beneficence in the context of the chiropractic profession. Beneficence is defined as an act of charity, mercy, and kindness with a strong connotation of doing good to others including moral obligation. All professionals have the foundational moral imperative of doing right. In the context of the professional-client relationship, the professional is obligated to, always and without exception, favor the well-being and interest of the client. In health care, beneficence is one of the fundamental ethics. An integral part of work as a professional is the foundational ethic of beneficence. An understanding of this ethic of care compels the individual health practitioner to consider his or her calling to the high standards of professionalism as a moral imperative; one that advocates for high standards and strives for the greater good. Health care professionals have a duty of care that extends to the patient, professional colleagues, and to society as a whole. Any individual professional who neither understands nor accepts this duty is at risk for acting malevolently and violating the fiduciary principle of honoring and protecting the patient.


A shadowing program for PAs and APRNs to promote collaborative care.
This article describes a shadowing program aimed at promoting collaborative care among PAs and NPs at an academic medical center. The program fostered interprofessional and interdisciplinary experiences to improve collaborative skills. Clinicians who completed the program had a significant improvement in collaborative competencies, as measured by the Interprofessional Collaboration Competency Attainment Survey.


[Extracorporeal membrane oxygenation for acute respiratory failure induced by Legionella pneumoniae. (Case report)].
We report a case of severe legionella pneumonia with acute respiratory failure, successfully managed with veno-venous extracorporeal membrane oxygenation (VV-ECMO). The patient presented with 4-day history of fever and cough. He was in critical condition, with exacerbated respiratory failure. Mechanical ventilation, volume replacement and antibiotic therapy were initiated. Despite increasing mechanical ventilatory support (FiO2 100%, TV 10 ml/kg, f 30/min, PEEP 5 cmH20), PaO2 fell below 40Torr and life sustaining measures were undertaken. VV-ECMO (flow 30 ml/kg/min) was commenced, and the patient responded well, with an elevation of PaO2. Erythromycin therapy was effective against the pneumonia. VV-ECMO was maintained for 92 hours, mechanical ventilation was successfully discontinued 11 days after and the patient was discharged 82 days after cessation of ventilator support. Serum antibody examination proved legionella infection. VV-ECMO may have a role in the management of patients with acute respiratory failure caused by bacterial pneumonia.


The effects of delayed reinforcement on variability and repetition of response sequences.
Four experiments examined the effects of delays to reinforcement on key peck sequences of pigeons maintained under multiple schedules of contingencies that produced variable or repetitive behavior. In Experiments 1, 2, and 4, in the repeat component only the sequence right-right-left-left earned food, and in the vary component four-response sequences different from the previous 10 earned food. Experiments 1 and 2 examined the effects of nonresetting and resetting delays to reinforcement, respectively. In Experiment 3, in the repeat component sequences had to be the same as one of the previous three, whereas in the vary component sequences had to be different from each of the previous three for food. Experiment 4 compared postreinforcer delays to prereinforcement delays. With immediate reinforcement sequences occurred at a similar rate in the two components, but were less variable in the repeat component. Delays to reinforcement decreased the rate of sequences similarly in both components, but affected variability differently. Variability increased in the repeat component, but was unaffected in the vary component. These effects occurred regardless of the manner in which the delay to reinforcement was programmed or the contingency used to generate repetitive behavior. Furthermore, the effects were unique to prereinforcement delays.


Circular CT in combination with a helical segment.
The combination of circular CT with a helical trajectory segment results in a mathematically complete data set. We present a reconstruction algorithm which is mathematically exact and of the filtered back-projection type. The algorithm ensures that only Radon planes which are not covered along the circle are taken into account, when data from the helical segment are back-projected. Therefore, the helical segment contributes only to low-frequency parts of trans-axial slices. Data along the helix can be obtained with a very low acquisition dose.


Hypersensitivity to antiretroviral drugs.
Background. Antiretroviral therapy (ART) may be responsible for hypersensitivity reactions varying in severity, clinical manifestations and frequency. Case report. We report the case of a 47-year-old woman with HIV infection who developed a delayed mucocutaneous reaction after treatment with ART. Hypersensitivty reaction (HR) to emtricitabine and tenofovir was considered probable based on positive patch tests (PT) and hypersensitivity reaction to nevirapine was confirmed by drug provocation test. Discussion. The diagnosis of HR to ART remains a diagnostic challenge, partly due to unknown mechanism and the absence of validated diagnostic tools. Patch testing may represent a useful method for confirming hypersensitivity. Further investigation in this area is required, so that successful management strategies can be offered, preventing loss of potent and viable antiretroviral agents.


Cascade Synthesis of Fluorinated Spiroheterocyclic Scaffolding for Peptidic Macrobicycles.
Octafluorocyclopentene (OFCP) engages linear, unprotected peptides in polysubstitution cascades that generate complex fluorinated polycycles. The reactions occur in a single flask at 0-25 °C and require no catalysts or heavy metals. OFCP can directly polycyclize linear sequences using native functionality, or fluorospiroheterocyclic intermediates can be intercepted with exogenous nucleophiles. The latter tactic generates molecular hybrids composed of peptides, sugars, lipids, and heterocyclic components. The platform can create stereoisomers of both single- and double-looped macrocycles. Calculations indicate that the latter can mimic diverse protein surface loops. Subsets of the molecules have low energy conformers that shield the polar surface area through intramolecular hydrogen bonding. A significant fraction of OFCP-derived macrocycles tested show moderate to high passive permeability in parallel artificial membrane permeability assays.


Differentially expressed plasma proteins of β-thalassemia/hemoglobin E patients in response to curcuminoids/vitamin E antioxidant cocktails.
Iron overload and oxidative stress are the major causes of serious complications and mortality in thalassemic patients. Our previous work supports the synergistic effects of antioxidant cocktails (curcuminoids or vitamin E, N-acetylcysteine, and deferiprone) in treatment of β-thalassemia/Hb E patients. This further 2-DE-based proteomic study aimed to identify the plasma proteins that expressed differentially in response to antioxidant cocktails. Frozen plasma samples of ten normal subjects and ten β-thalassemia/Hb E patients at three-time points (baseline, month 6, and month 12) were reduced the dynamic range of proteome using ProteoMiner kit and separated proteins by two-dimensional gel electrophoresis. Differentially expressed proteins were identified using tandem mass spectrometry. Several plasma proteins were validated by ELISA and Western blot analysis. Thirteen and 11 proteins were identified with altered expression levels in the curcuminoids- and vitamin E cocktail groups, respectively. The associations between vitronectin (VTN) expression and total bilirubin levels, as well as between serum paraoxonase/arylesterase 1 (PON1) expression and blood reactive oxygen species were observed. Validation results were consistent with proteomics results. These plasma proteins may provide better understanding of the mechanisms underlying the therapeutic effects of antioxidant cocktails in thalassemic patients.


[Silica in ceramic industry: exposition and pulmonary diseases].
Since 1990, a cohort survey has been carried out among workers employed in pottery workers by the Local Health Unit of Viterbo, Latium (Italy). Cumulative exposure to silica containing dust has been assessed for 808 workers, who were also screened with a questionnaire on respiratory symptoms, chest radiography and lungfunction tests. The prevalence of small opacities 1/0 and 1/1+ was 3.0% and 4.1% respectively and the prevalence increased with the cumulative exposure. A close relationship has been found between silica dose and decrease in lung function.


Safety and danger of biologic treatments in psoriasis in context of cutaneous T-cell lymphoma (CTCL).
Microenvironment has a significant impact on the pathogenesis of cutaneous T-cell lymphoma (CTCL), especially in the context of new emerging biologic therapies. Our aim was to review the literature on interleukins 12, 17, 23 and tumour necrosis factor-α in mycosis fungoides in order to clarify the safety of using biologics in the treatment of psoriasis. Our analysis suggests that these drugs may have an impact on the progression of CTCL. Concluding, in case of uncertain psoriatic lesions, a biopsy followed by pathologic examination should exclude the possibility of co-existence of a primary cutaneous lymphoma before administration of therapies affecting cytokine profiles.


[Lead compound optimization strategy (3)--Structure modification strategies for improving water solubility].
Water solubility is an essential physical chemistry property of organic small molecule drug and is also a very important issue in drug discovery. Good water solubility often leads to a good drug potency and pleasant pharmacokinetic profiles. To improve water solubility, structure modification is a straight and effective way based on the theory of water solubility. This review summarized valid structure modification strategies for improving water solubility including salt formation, polar group introduction, liposolubility reduction, conformation optimization and prodrug.


Mucormycosis of the jaw after dental extractions: two case reports.
Mucormycosis is a rare opportunistic fungal infection, which is mainly reported to occur in patients with immunocompromised conditions such as uncontrolled diabetes mellitus and leukaemias. In this paper, two cases of mucormycosis are reported after dental extractions. The first case of mucormycosis occurred in the maxilla and mandible of a 14 year old male patient undergoing chemotherapy for acute myeloid leukaemia. The second case occurred in the mandible of a 49 year old male patient with a recently diagnosed type-2 diabetes mellitus, presenting with ketoacidosis and underlying undiagnosed acute lymphoblastic leukaemia. The outcome of these reported cases of mucormycosis was favourable after comprehensive surgical and medical management.


[A nationwide survey on paraneoplastic neurological syndromes. Project group on paraneoplastic neurological syndromes, Neuroimmunological Disease Research Committee, the Ministry of Health and Welfare, Japan].
A nationwide survey on paraneoplastic neurological syndrome was carried out using enquiry sheets for neurologists in hospitals to examine the approximate number of patients, clinical features, characteristic anti-neuronal antibodies, accompanying malignancy and current therapies of these syndromes. In the present survey, 159 case records of this syndrome were accumulated. The major clinical variations were as follows: sensory neuropathy (54 cases; 34%), Lambert-Eaton myasthenic syndrome (45 cases; 28%) including 5 cases complicated with subacute cerebellar degeneration (PCD), PCD (40 cases; 25%) and limbic encephalitis (8 cases; 5%). Neurological symptoms preceded diagnosis of malignancy in over 83% of the total cases of these four major clinical variations in which tumors were verified. The detection of anti-neuronal antibodies, which are characteristic of some clinical types of this syndrome, is very important for early diagnosis and treatment for the neurological symptoms and underlying malignancy.


[Gabriel Trompiz and the institutionalization of science in Venezuela].
A testimonial to Dr. Trompiz, owing to the first lustrum of his death (August 23th, 1895). He was born in Falcon State (1907), graduated as medical doctor at UCV (1932) and postgraduated in Germany and Spain. Several analyses are made in order to consider D'Trompiz' position on the poor situation of science in Venezuela: 1) The historical comparison of science between Europe and Latin America; 2) The work presented by Garcia Gallo in the UNESCO Conference (Chile, 1965); 3) The H. Jaguaribe's work in CORDIPLAN (1974); 4) The Santis' evaluation on scientific investigation in our country.


Feasibility and Safety of Radiofrequency Ablation Guided by Bronchoscopic Transparenchymal Nodule Access in Canines.
The treatment of pulmonary malignancies remains a challenge. The efficacy and safety of bronchoscopic radiofrequency ablation (RFA) for the treatment of lung cancer are not well elucidated. This study aimed to evaluate the feasibility and safety of RFA guided by bronchoscopic transparenchymal nodule access (BTPNA) in vivo. In an attempt to determine the parameters of RFA, we first performed RFA in conjunction with automatic saline microperfusion in the lung in vitro with various ablation energy (10, 15, 20, 25, and 30 W) and ablation times (3, 5, 8, and 10 min). The correlation between ablated area and RFA parameter was recorded and analyzed. Further, we conducted a canine study with RFA by BTPNA in vivo, observing the ablation effect and morphological changes in the lung assessed by chest CT and histopathologic examination at various follow-up time points (1 day, n = 3; 30 days, n = 4; 90 days, n = 4). The related complications were also observed and recorded. More ablation energy, but not ablation time, induced a greater range of ablation area in the lung. Ablation energy applied with 15 W for 3 min served as the appropriate setting for pulmonary lesions ≤1 cm. RFA guided by BTPNA was performed in 11 canines with 100% success rate. Inflammation, congestion, and coagulation necrosis were observed after ablation, which could be repaired within 7 days; subsequently, granulation and fibrotic scar tissue developed after 30 days. No procedure-related complication occurred during the operation or in the follow-up periods. The novel RFA system and catheter in conjunction with automatic saline microperfusion present a safe and feasible modality in pulmonary parenchyma. RFA guided by BTPNA appears to be well established with an acceptable tolerance; it might further provide therapeutic benefit in pulmonary malignancies.


Dysphonia - the single symptom of rifampicin resistant laryngeal tuberculosis.
Tuberculosis is still the most frequent granulomatous laryngeal disease. Absence of pathognomonic symptoms and change in clinical pattern frequently leads to misdiagnosis and delayed treatment. Hoarseness is the commonest symptom of laryngeal tuberculosis and constitutional symptoms are usually rare. However dysphonia can be caused by many other more common conditions. Hoarseness can be a symptom of organic (nodules and polyps of vocal folds, tumors, vocal fold paresis) or functional (functional dysphonia, laryngeal conversion disorder, paradoxical vocal folds motion) conditions. Rarely systemic diseases as amyloidosis, sarcoidosis, Wegener's granulomatosis or tuberculosis can cause vocal dysfunction too. That is why laryngeal tuberculosis is often forgotten in case of persistent hoarseness. In this article, we present a case of a young previously healthy woman, complaining of persistent hoarseness with no other leading symptoms. Though endoscopic image suggested a malignancy, histology showed granulomatous lesion. Detailed examination revealed laryngeal and pulmonary tuberculosis resistant to rifampicin. Dysphonia can be the only one symptom of laryngeal tuberculosis. The disease should be taken into consideration when a patient complains of persistent hoarseness in order to avoid delays in treatment and spread of infection.


Modified Technique for Scleral-Sutured Fixation with the Double Knots Technique for Posterior Chamber Intraocular Lens: Short-Term Observation.
To evaluate the short-term safety and efficacy of a novel approach of utilizing the 9-0 looped polypropylene suture with double knots buried into the scleral groove and the scleral tunnel to minimize the risk of the suture erosion and suture knot exposure. Clinical-based retrospective study. Records of consecutive patients who had anterior vitrectomy and scleral-fixated posterior chamber intraocular lens (IOL) implantation between July 2018 and April 2020 with a minimum follow-up of 3 months were reviewed. This study enrolled a total of 21 eyes from 20 patients (15 male). These patients had a mean age of 58.52 ± 8.55 years and were followed for an average of 1.08 ± 0.58 years postoperatively. Best-corrected visual acuity (BCVA) improved from a preoperative mean of 0.43 ± 0.41 logMAR to a significantly higher mean 3-month postoperative value of 0.09 ± 0.21 logMAR (Z = -3.35, p < 0.01). There were no statistical differences between the preoperative and postoperative corneal endothelial cell density (p=0.71). The postoperative complications included transient increased intraocular pressure in 5 eyes (24%). No other complications were detected during the follow-up. The modified technique proposed is a safe, effective, and reliable approach resulting in good visual outcomes. Our procedure might have the potential benefit to avoid suture-related complications in scleral-fixated IOL implantation. Trial registration. Retrospective case series study, not applicable.


Computational Approach to Annotating Variants of Unknown Significance in Clinical Next Generation Sequencing.
Next generation sequencing (NGS) has become a common technology in the clinical laboratory, particularly for the analysis of malignant neoplasms. However, most mutations identified by NGS are variants of unknown clinical significance (VOUS). Although the approach to define these variants differs by institution, software algorithms that predict variant effect on protein function may be used. However, these algorithms commonly generate conflicting results, potentially adding uncertainty to interpretation. In this review, we examine several computational tools used to predict whether a variant has clinical significance. In addition to describing the role of these tools in clinical diagnostics, we assess their efficacy in analyzing known pathogenic and benign variants in hematologic malignancies.


Water Dynamics Around Proteins: T- and R-States of Hemoglobin and Melittin.
The water dynamics, as characterized by the local hydrophobicity (LH), is investigated for tetrameric hemoglobin (Hb) and dimeric melittin. For the T0 to R0 transition in Hb, it is found that LH provides additional molecular-level insight into the Perutz mechanism, i.e., the breaking and formation of salt bridges at the α1/β2 and α2/β1 interface is accompanied by changes in LH. For Hb in cubic water boxes with 90 and 120 Å edge length it is observed that following a decrease in LH as a consequence of reduced water density or change of water orientation at the protein/water interface the α/β interfaces are destabilized; this is a hallmark of the Perutz stereochemical model for the T to R transition in Hb. The present work thus provides a dynamical view of the classical structural model relevant to the molecular foundations of Hb function. For dimeric melittin, earlier results by Cheng and Rossky [ Nature 1998, 392, 696-699] are confirmed and interpreted on the basis of LH from simulations in which the protein structure is frozen. For the flexible melittin dimer, the changes in the local hydration can be as much as 30% greater than for the rigid dimer, reflecting the fact that protein and water dynamics are coupled.


A crystalline tri-thorium cluster with σ-aromatic metal-metal bonding.
Metal-metal bonding is a widely studied area of chemistry1-3, and has become a mature field spanning numerous d transition metal and main group complexes4-7. By contrast, actinide-actinide bonding, which is predicted to be weak8, is currently restricted to spectroscopically detected gas-phase U2 and Th2 (refs. 9,10), U2H2 and U2H4 in frozen matrices at 6-7 K (refs. 11,12), or fullerene-encapsulated U2 (ref. 13). Furthermore, attempts to prepare thorium-thorium bonds in frozen matrices have produced only ThHn (n = 1-4)14. Thus, there are no isolable actinide-actinide bonds under normal conditions. Computational investigations have explored the probable nature of actinide-actinide bonding15, concentrating on localized σ-, π-, and δ-bonding models paralleling d transition metal analogues, but predictions in relativistic regimes are challenging and have remained experimentally unverified. Here, we report thorium-thorium bonding in a crystalline cluster, prepared and isolated under normal experimental conditions. The cluster exhibits a diamagnetic, closed-shell singlet ground state with a valence-delocalized three-centre-two-electron σ-aromatic bond16,17 that is counter to the focus of previous theoretical predictions. The experimental discovery of actinide σ-aromatic bonding adds to main group and d transition metal analogues, extending delocalized σ-aromatic bonding to the heaviest elements in the periodic table and to principal quantum number six, and constitutes a new approach to elaborate actinide-actinide bonding.


Matrix-assisted laser desorption ionization time-of-flight mass spectrometry: a powerful tool for the mass and sequence analysis of natural and modified oligonucleotides.
We report the analysis and characterization of natural and modified oligonucleotides by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The present technology was highly improved for this class of compounds by using a new matrix, 2,4,6-trihydroxy acetophenone, together with di- and triammonium salts of organic or inorganic acids to suppress peak broadening due to multiple ion adducts. This methodology can be used in combination with time dependent degradation of oligonucleotides by exonucleases as powerful tool to determine sequence compositions.


Paediatric surgical training: a system that works.
Paediatric surgical trainees going through the system at the Royal Children's Hospital (RCH), Melbourne, have been impressed with the amount of time dedicated to postgraduate training compared with other institutions. They generally felt well prepared to sit for Fellowship examinations. We decided to look at the programme offered at the RCH and objectively assess the results. A review was undertaken of the training system at the RCH. Opinions were sought from recent and current trainees and compared with trainees in other disciplines. Figures were obtained from the RACS Examinations Office with respect to pass rates at Fellowship examinations. The training programme is outlined in some detail. A total of 79% of candidates passed their FRACS in paediatric surgery while at the RCH since 1985, compared with 52% from all other institutions. A successful training programme requires a commitment to educate one's junior colleagues. Busy consultants can contribute actively by offering to teach and by encouraging their trainees to attend rounds and tutorials. The rewards are better-educated and well-rounded surgeons as well as, hopefully, a higher pass-rate at the Part 2 examination.


Photochemical grafting and patterning of biomolecular layers onto TiO2 thin films.
TiO2 thin films are highly stable and can be deposited onto a wide variety of substrate materials under moderate conditions. We demonstrate that organic alkenes will graft to the surface of TiO2 when illuminated with UV light at 254 nm and that the resulting layers provide a starting point for the preparation of DNA-modified TiO2 thin films exhibiting excellent stability and biomolecular selectivity. By using alkenes with a protected amino group at the distal end, the grafted layers can be deprotected to yield molecular layers with exposed primary amino groups that can then be used to covalently link DNA oligonucleotides to the TiO2 surface. We demonstrate that the resulting DNA-modified surfaces exhibit excellent selectivity toward complementary versus noncomplementary target sequences in solution and that the surfaces can withstand 25 cycles of hybridization and denaturation in 8.3 M urea with little or no degradation. Furthermore, the use of simple masking methods provides a way to directly control the spatial location of the grafted layers, thereby providing a way to photopattern the spatial distribution of biologically active molecules to the TiO2 surfaces. Using Ti films ranging from 10 to 100 nm in thickness allows the preparation of TiO2 films that range from highly reflective to almost completely transparent; in both cases, the photochemical grafting of alkenes can be used as a starting point for stable surfaces with good biomolecular recognition properties.


[A Case of Rectal Cancer Suspectedly Recurred Seventeen Years after EMR].
We report a case of a 73-year-old man who underwent endoscopic mucosal resection (EMR) for early rectal cancer(i ntramucosal cancer)at other hospital 17 years ago. Ten years later, he underwent a total colonoscopy, which showed no recurrence of the tumor. Twelve years later, a mass with calcification was incidentally detected in front of the sacrum, which was diagnosed as a benign tumor at that time. Seventeen years later, he presented with constipation and diarrhea, and was detected of a sub-circumferential tumor in the rectum by a total colonoscopy. Biopsy revealed that the tumor was malignancy. CT showed a mass in the left lateral liver lobe. The mass was suspected of metastasis. Laparoscopic super lower anterior resection was performed for rectal cancer, and pathological examination showed that the tumor was pT4a, N3, M1(H), Stage Ⅳa. One month after surgery, laparoscopic hepatectomy was performed for liver metastasis. Six months after surgery, CT showed multiple lung metastases. He continues to undergo chemotherapy. Although this case was treated with EMR for intramucosal carcinoma, clinical history and pathological findings suggested local recurrence.


Efficacy of umbilical cord cleansing with a single application of 4% chlorhexidine for the prevention of newborn infections in Uganda: study protocol for a randomized controlled trial.
Yearly, nearly all the estimated worldwide 2.7 million neonatal deaths occur in low- and middle-income countries. Infections, including those affecting the umbilical cord (omphalitis), are a significant factor in approximately a third of these deaths. In fact, the odds of all-cause mortality are 46% higher among neonates with omphalitis than in those without. Five large randomized controlled trials in Asia and Sub-Saharan Africa (SSA) have examined the effect of multiple cord stump applications with 4% chlorhexidine (CHX) for at least 7 days on the risk of omphalitis and neonatal death. These studies, all community-based, show that multiple CHX applications reduced the risk of omphalitis. Of these trials, only one study from South Asia (the Bangladeshi study) and none from Africa examined the effect of a single application of CHX as soon as possible after birth. In this Bangladeshi trial, CHX led to a reduction in the risk of mild-moderate omphalitis and neonatal death. It is important, in an African setting, to explore the effect of a single application among health-facility births. A single application is programmatically much simpler to implement than daily applications for 7 days. Therefore, our study compares umbilical cord cleansing with a single application of 4% CHX at birth with dry cord care among Ugandan babies born in health facilities, on the risk of omphalitis and severe neonatal illness. The CHX study is a facility-based, individually randomized controlled trial that will be conducted among 4760 newborns in Uganda. The primary outcomes are severe illness and omphalitis during the neonatal period. Analysis will be by intention-to-treat. This study will provide novel evidence, from a Sub-Saharan African setting, of the effect of umbilical cord cleansing with a single application of 4% CHX at birth and identify modifiable risk factors for omphalitis. ClinicalTrials.gov, identifier: NCT02606565 . Registered on 12 November 2015.


Effects of smoke exposure and other lifestyle factors on pain response to electrical stimulation in women.
A relationship between smoking and development of pain syndromes has been suggested in the literature. The present study examined associations between smoke exposure and other related variables, and pain response to suprathreshold electrical stimulation. Subjects were prospectively recruited from a population referred to an electrodiagnostic clinic. Information about age, smoke exposure, caffeine and alcohol consumption was obtained, as well as documented objective signs of stress through physical assessment. One investigator applied two standardized 0.1 ms electrical stimulations (50 mA followed by 100 mA) to asymptomatic extremities at the beginning of each electrodiagnostic session, using consistent technique. Subjects used a visual analogue scale to indicate the level of pain felt after each stimulation. Two hundred fifteen women were included. Current smokers and those currently exposed to second-hand smoke had significantly higher pain ratings (P=0.003 for 50 mA, P=0.005 for 100 mA) than those not currently exposed to smoke. Time since exposure was negatively associated with pain ratings. Those with objective signs of stress reported higher levels of pain, which was significant for the 100 mA stimulation (P=0.046). Linear regression modelling indicated that current smoke exposure and alcohol use were associated with higher pain ratings at both 50 mA and 100 mA, while stress was associated with higher pain ratings and older age was associated with lower pain ratings at 100 mA only. Exposure to cigarette smoke is significantly related to higher reported levels of pain experienced in response to electrical stimulation in this study population. Exposure to smoke can add 10 points to the 100-point visual analogue scale compared with subjects without exposure, with alcohol use adding another eight points. Reported pain decreases as length of time since previous exposure to smoke increases.


Molecular fingerprints in the hippocampus of alcohol seeking during withdrawal.
Alcohol use disorder (AUD) is characterized by pathological motivation to consume alcohol and cognitive inflexibility, leading to excessive alcohol seeking and use. Due to limited understanding of the molecular basis of the disease, there are few pharmacological interventions available to combat AUD. In this study, we aimed to investigate the molecular correlates of impaired extinction of alcohol seeking during alcohol withdrawal using a mouse model of AUD implemented in the automated IntelliCage social system. This model enabled us to distinguish between animals exhibiting AUD-prone and AUD-resistant phenotypes, based on the presence of ≥ 2 or < 2 criteria of AUD, respectively. We utilized new generation RNA sequencing to identify genes that were differentially expressed in the hippocampus and amygdala of mice meeting ≥ 2 or < 2 criteria, as these brain regions are implicated in alcohol motivation, seeking, consumption and the cognitive inflexibility characteristic of AUD. To complement the sequencing studies, we conducted ex vivo electrophysiology experiments. Our findings revealed significant dysregulation of the hippocampal genes associated with the actin cytoskeleton and synaptic function, including actin binding molecule cofilin, during alcohol withdrawal in mice meeting ≥ 2 criteria compared to those meeting < 2 criteria. Moreover, this dysregulation was accompanied by impaired synaptic transmission in the molecular layer of the hippocampal dentate gyrus (ML-DG). Additionally, we demonstrated that overexpression of cofilin in the polymorphic layer of the hippocampal dentate gyrus (PoDG) inhibited ML-DG synapses, increased motivation to seek alcohol, impaired extinction of alcohol seeking and increased correlation between AUD behaviors, resembling the phenotype observed in mice meeting ≥ 2 criteria. Overall, our study uncovers a novel mechanism linking increased hippocampal cofilin expression with the AUD phenotype.


Recent Advances in Nanoparticle-Mediated Delivery of Anti-Inflammatory Phytocompounds.
Phytocompounds have been used in medicine for decades owing to their potential in anti-inflammatory applications. However, major difficulties in achieving sustained delivery of phyto-based drugs are related to their low solubility and cell penetration, and high instability. To overcome these disadvantages, nanosized delivery technologies are currently in use for sustained and enhanced delivery of phyto-derived bioactive compounds in the pharmaceutical sector. This review focuses on the recent advances in nanocarrier-mediated drug delivery of bioactive molecules of plant origin in the field of anti-inflammatory research. In particular, special attention is paid to the relationship between structure and properties of the nanocarrier and phytodrug release behavior.


The influence of divergent growth selection of semen traits, fertility and hatchability.
The effects of divergent growth selection for 18 generations on semen characteristics, fertility and hatchability were investigated. Males from the low weight line produced semen with a significantly (P less than or equal to 0.05) higher sperm concentration and a highly significantly (P less than or equal to 0.01) lower methylene blue reduction time than the males from the high line. Differences between lines for semen volume, sperm motility, percent of live sperm, fertility and hatchability were not statistically significant.


Effects of interventions for the treatment of nocturnal enuresis in children.
The effectiveness of interventions for the treatment of nocturnal enuresis in children published in a recent issue of Effective Health Care is reviewed.


Lumbar foraminal neuropathy: an update on non-surgical management.
Lumbar foraminal pathology causing entrapment of neurovascular contents and radicular symptoms are commonly associated with foraminal stenosis. Foraminal neuropathy can also be derived from inflammation of the neighboring lateral recess or extraforaminal spaces. Conservative and interventional therapies have been used for the treatment of foraminal inflammation, fibrotic adhesion, and pain. This update reviews the anatomy, pathophysiology, clinical presentation, diagnosis, and current treatment options of foraminal neuropathy.


The effect of oxidative stress polymorphisms on the association between long-term black carbon exposure and lung function among elderly men.
Black carbon (BC) is a pro-oxidant, traffic-related pollutant linked with lung function decline. We evaluated the influence of genetic variation in the oxidative stress pathway on the association between long-term BC exposure and lung function decline. Lung function parameters (FVC and FEV1) were measured during one or more study visits between 1995 and 2011 (n=651 participants) among an elderly cohort: the Normative Aging Study. Residential BC exposure levels were estimated using a spatiotemporal land use regression model. We evaluated whether oxidative stress variants, combined into a genetic score, modify the association between 1-year and 5-year moving averages of BC exposure and lung function levels and rates of decline, using linear mixed models. We report stronger associations between long-term BC exposure and increased rate of lung function decline, but not baseline lung function level, among participants with higher oxidative stress allelic risk profiles compared with participants with lower risk profiles. Associations were strongest when evaluating 5-year moving averages of BC exposure. A 0.5 µg/m(3) increase in 5-year BC exposure was associated with a 0.1% yearly increase in FVC (95% CI -0.5 to 0.7) among participants with low genetic risk scores and a 1.3% yearly decrease (95% CI -1.8 to -0.8) among those with high scores (p-interaction=0.0003). Our results suggest that elderly men with high oxidative stress genetic scores may be more susceptible to the effects of BC on lung function decline. The results, if confirmed, should inform air-quality recommendations in light of a potentially susceptible subgroup.


Relevance of KCNJ5 in Pathologies of Heart Disease.
Abnormalities in G-protein-gated inwardly rectifying potassium (GIRK) channels have been implicated in diseased states of the cardiovascular system; however, the role of GIRK4 (Kir3.4) in cardiac physiology and pathophysiology has yet to be completely understood. Within the heart, the KACh channel, consisting of two GIRK1 and two GIRK4 subunits, plays a major role in modulating the parasympathetic nervous system's influence on cardiac physiology. Being that GIRK4 is necessary for the functional KACh channel, KCNJ5, which encodes GIRK4, it presents as a therapeutic target for cardiovascular pathology. Human variants in KCNJ5 have been identified in familial hyperaldosteronism type III, long QT syndrome, atrial fibrillation, and sinus node dysfunction. Here, we explore the relevance of KCNJ5 in each of these diseases. Further, we address the limitations and complexities of discerning the role of KCNJ5 in cardiovascular pathophysiology, as identical human variants of KCNJ5 have been identified in several diseases with overlapping pathophysiology.


Access to Functionalized Luminescent Multi-2,2':6',2″-terpyridine Ligands.
A one-pot synthesis of substituted multi-2,2':6',2″-terpyridines (multi-tpy) has been achieved using an acetylquaterpyridine precursor with various aryl aldehydes in basic media. This strategy enables ready access to functionalized tri-terpyridines. Utilizing a Suzuki-type cross-coupling, larger structures such as tetra- or even hexa-tpy were obtained from our tri-tpy precursor. These macromolecular units are ideal building blocks for the construction of transition-metal-based supramolecular assemblies.


Rapid determination of alpha-fetoprotein in amniotic fluid using an automated immunoturbidimetric technique.
A rapid and precise immunoturbidimetric assay for the measurement of alpha-fetoprotein in amniotic liquor has been developed. The method is an 'end-point' technique without blank correction since non-specific turbidity does not occur with amniotic liquor. The assay is able to distinguish 4 mg/l from zero and is unaffected by gross blood staining of the liquor. The protocol requires a duplicate analysis of the liquor to detect high levels of alpha-fetoprotein.


Systems biology and the mathematical modelling of antibody-directed enzyme prodrug therapy (ADEPT).
Antibody-directed enzyme prodrug therapy (ADEPT) can generate highly localised concentrations of cytotoxic agents directly in a tumour, thereby reducing the collateral toxicity associated with normal tissue exposure. ADEPT is a two-component approach. First, a non-toxic antibody-enzyme fusion protein is localised in the tumour matrix by binding a specific antigen expressed only on the surface of a cancer cell. Once the fusion protein is bound, an inert small molecule prodrug is administered which is the substrate for the enzyme bound to the tumour surface. When the prodrug comes into contact with the bound enzyme, an active cytotoxic agent is generated. A multiple length-scale model of ADEPT therapy in solid tumours is presented. A four-compartment pharmacokinetic (PK) model is formulated where the tumour is comprised of interstitial and cell-surface subcompartments. The macroscopic PK model which describes the biodistribution of antibody-enzyme conjugate, prodrug and active drug at the largest length scale is coupled to a reaction-diffusion tumour model. The models are qualitatively validated against current literature and experimental understanding. The relationship between tumour localisation and the affinity of the antibody-enzyme conjugate for its surface antigen is explored by simulation. The influence of pharmacokinetic and biophysical parameters such as renal elimination rate and permeability of the tumour vasculature upon tumour uptake and retention of the fusion protein are also explored. Lastly, a technique for establishing an optimal prodrug dosing schedule is formulated and initial simulation results are presented.


Investigation of magnetic properties induced by group-V element in doped ZnO.
For the potential applications in spintronics, we examine systematically the electronic properties of group-V elements (X) doped ZnO to investigate the magnetic properties induced by X based on density functional theory calculations. Our results indicates that X atoms doped in the form of a substitutional X atom at an O anion site (XO) and at a Zn cation site combining with two Zn vacancies (XZn-2VZn complex) under different circumstances can introduce magnetism. The magnetism comes from the p-p and p-d coupling interaction between the dopant X-p orbitals and the host O-2p and Zn-3d orbitals. The stability of the ferromagnetism (FM) phase induced by XO defects decreases with the increase of dopant atomic number due to the lower electronegativity value, which can be interpreted by the phenomenological band-coupling model. The origin of the magnetism induced by XZn-2VZn is similar to that of the Zn vacancy (VZn) in ZnO and comes from the O-2p orbitals dominantly. The FM stability introduced by XZn-2VZn decreases with the order N < Sb < As < P, which is ascribed to the delocalization of the O-2p orbitals. The results mean that 3p/4p/5p dopants could also make ZnO materials into diluted magnetic semiconductors.


Nutritional behaviours and body self-perception in polish pupils attending middle-school.
Adolescence is a vital part of child development, where acquired eating/dietary behaviour is often associated with ones' perception of body shape. To assess eating habits in relation to body shape perception and esteem in middle-school (junior-high) pupils. Surveyed subjects were 170 middle-school pupils from Warsaw; 101 girls and 69 boys aged 15 years. An anonymous questionnaire was used to determine eating habits, body mass, growth and body shape perception. Anthropometric measurement cut-off points were taken according to the method of Cole et al. Only 29% of pupils ate 5 daily meals; of whom there were significantly more girls than boys (35% vs 20%, p = 0.042). Girls more often consumed second breakfast than boys (p < 0.001), whilst boys ate dinner more frequently than girls (p = 0.004). Eating meals was observed in 86% all pupils, where sweets (71%) and fresh fruit (69%) were most commonly eaten. Boys ate fast-food more often than girls (p = 0.004), as well as savoury snacks (p = 0.002), sweets (p = 0.009) and sweetened fizzy drinks (p < 0.001). Girls however, consumed more low-fat foodstuffs compared to boys (p = 0.003). Over- weight was more common in boys than girls (26% vs 9%, p = 0.003), whereas girls were more frequently malnourished than boys (21% vs 7%, p = 0.016). Far fewer girls were satisfied with their body shape compared to boys (51% vs 94%, p < 0.001). Girls also more commonly expressed a desire for slimming, despite either having a correct body mass or being underweight. Many adverse and abnormal eating habits of pupils were found, especially in boys, that could lead to over- weight and obesity. Subjects were found to incorrectly assess their body shape, particularly the girls, thereby leading to unwarranted slimming behaviour. nutritional habits, middle-school pupils, perceived body shape/image.


Changes in Pharyngeal Airway Space and Craniocervical Angle after Anterior Bimaxillary Subapical Osteotomy.
This study explored the effects of genioplasty (Gep) and anterior subapical osteotomy of the maxilla and mandible (ASOMx+ASOMd) on the pharyngeal airway dimensions of patients with bimaxillary protrusion (BiP). Thirty-two patients were divided into 2 groups. Group 1 received ASOMx+ASOMd, and group 2 received ASOMx+ASOMd+Gep. The cephalograms of the patients were collected before surgery and 2 months after surgery. Changes in the landmarks, related cephalometric angles (gonial, SN-GoGn, Y-axis, and SN-C2C4 angles), and 2 pharyngeal airway dimensions (uvulo-pharyngeal airway [UOP] and tongue-pharyngeal airway [TOP]) were analyzed. Before surgery, the parameters (incisor superius, incisor inferius, menton, most superior and anterior point of the hyoid bone, tip of the uvula, inferoanterior point on the second cervical vertebra, and inferoanterior point on the fourth cervical vertebra) and measured angles (SNA, SNB, ANB, gonial, SN-GoGn, Y-axis, and C4C2-SN) of both groups showed no significant differences. Following ASOMx, the patients in groups 1 and 2 exhibited a setback by 7.0 and 6.6 mm, respectively. After ASOMd, groups 1 and 2 exhibited 4.9 and 5.3 mm setbacks, respectively. No significant difference in the amount of setback was observed between groups 1 and 2. The postoperative horizontal and vertical positions of Me in group 2 were significantly forward by 6.1 mm and upward by 1.5 mm, respectively. Regarding pharyngeal airway dimensions, TOP was decreased in group 1 (1.7 mm) and group 2 (1.3 mm). In the postoperative Pearson correlation coefficient test, the horizontal and vertical positions of Me showed no significant correlation with TOP in both groups. Therefore, Gep did not prevent the reduction of TOP in group 2. After bimaxillary anterior subapical osteotomy, the TOP of patients with BiP was decreased, and this situation was unavoidable, regardless of whether Gep was performed.


Pheromone-inducible expression of an aggregation protein in Enterococcus faecalis requires interaction of a plasmid-encoded RNA with components of the ribosome.
Transfer of the conjugative plasmid pCF10 from Enterococcus faecalis donor strains is induced by a peptide pheromone (cCF10) secreted by recipient cells. High-efficiency transfer requires expression of an aggregation protein (Asc10) encoded by the prgB gene and positively regulated by genes in a region 3-5 kb upstream, containing prgQ-R-S. Transcriptional fusion data reported here support the results of recent molecular analysis of the 5' ends of prgB transcripts which indicated that prgB transcription occurs by readthrough from the prgQ promoter. A 530-nucleotide prgQ-encoded RNA molecule (Q(L)) with rRNA-like domains is required for Asc10 production. Q(L) and cCF10 were found to interact with the L6 and S5 ribosomal proteins, respectively. Mutational analysis of Q(L) indicates that this RNA may also directly interact with 16S RNA. Q(L) is present in ribosomes translating the prgB message, and pheromone cCF10 may affect the association of this RNA with translation complexes. Results suggest that the positive regulatory molecules act post-transcriptionally on the polycistronic message and modify a ribosome population to enhance pheromone-induced translation of prgB.