Invading squamous cell carcinoma can retain a basal lamina. An immunohistochemical study using a monoclonal antibody to type IV collagen.
A monoclonal antibody to human glomerular type IV collagen has been characterized and used in an immunohistochemical study of the distribution of this basement membrane protein in dysplasias, intraepithelial carcinomas, and infiltrating squamous cell carcinomas. Four squamous carcinoma cell lines established as xenografts in nude mice were also examined. In normal epidermis and mucosae, the basement membrane was clearly defined and intact. In areas of intraepidermal carcinoma, the basal lamina as defined by the antibody was usually continuous, and defects were only present in areas associated with an inflammatory infiltrate. Invasive squamous cell carcinomas, regardless of the degree of differentiation had a clearly delineated basement membrane at the epithelial stromal interphase. In areas of invasion, far removed from the in situ component, there were protrusions of tumor cells through the basement membrane into the stroma. Other abnormalities of basement membrane production such as aggregation of basement membrane and reduplication of the basal lamina were also associated with the carcinomas. There was a similar distribution of basal lamina material in involved lymph nodes and in squamous cell carcinomas that were growing as xenografts in nude mice. Our studies suggest that the loss of basement membrane type IV collagen is not generally associated with invasive squamous cell carcinomas and is not likely to be useful in the assessment of early invasion in this tumor. The similar distribution of type IV collagen in the xenografts and in the infiltrating tumors suggests that this system, in conjunction with the use of the same cell lines in vitro, will provide a model with which to study the control of deposition of type IV collagen.


FOLFOX-4 stop and go and capecitabine maintenance chemotherapy in the treatment of metastatic colorectal cancer.
Patients with metastatic colorectal cancer (MCC) usually receive FOLFOX-4, or other oxaliplatin (L-HOP)-based regimens, until the occurrence of progressive disease, with an increase in the incidence of neurotoxicity which is correlated to the cumulative dose of L-HOP. The aim of this study was to evaluate if FOLFOX-4 stop and go and capecitabine maintenance chemotherapy is associated with a low incidence of severe neurotoxicity in the treatment of MCC patients. Thirty-three patients were treated with FOLFOX-4 (L-HOP 85 mg/m(2) day 1, leucovorin 200 mg/m(2), 5-fluorouracil bolus 400 mg/m(2) and 22 h 600 mg/m(2) days 1 and 2, every 2 weeks). Patients who achieved objective response (OR) or stable disease (SD) then received oral capecitabine 2,500 mg/m(2) days 1-14 every 3 weeks; L-HOP was reintroduced as soon as progression occurred. Twenty-eight of the 29 patients who achieved OR or SD then received capecitabine. FOLFOX-4 was reintroduced in 18 patients (56.2%). The median response duration (RD) was 9.2 months and median progression-free survival (PFS) was 8.6 months. Twenty-eight patients (87.5%) had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 1 patient (3.1%). FOLFOX-4 stop and go and capecitabine maintenance chemotherapy was associated with a very low incidence of grade 3 neurotoxicity. Although the number of patients enrolled was far too low for a definite conclusion, RD and PFS were comparable to those usually reported in the treatment of MCC patients.


Sparks as sub-nanosecond, broadband light switches.
We evaluate spark micro-discharges as the working element of laser switches that can operate on sub-nanosecond timescales, function over a broad range of wavelengths, and handle high laser power. Sparks were generated in room temperature argon at 11-51 bar and xenon at 3-11.6 bar. A continuous 405 nm wavelength laser light was focused through the spark gap, and its transmission was recorded by a high-speed photodiode. We demonstrate that the transition to opacity at the higher pressures is faster than our detection circuit's 90%-10% fall time of 400 ps, indicating that the true fall time is 100 ps or shorter. The challenges to be overcome to improve device reliability are identified.


Reproductive biology of black seabream Acanthopagrus schlegelii, threadfin porgy Evynnis cardinalis and red pargo Pagrus major in the northern South China Sea with consideration of fishery status and management needs.
The reproductive biology of three commercially significant seabream species (family: Sparidae) Acanthopagrus schlegelii, Evynnis cardinalis and Pagrus major, taken from Hong Kong and adjacent northern South China Sea (SCS) waters, were investigated for their sexual patterns, spawning seasons, length at maturity and exploitation in relation to their conservation and management status. Histological analysis showed E. cardinalis and P. major to be functionally gonochoristic, the latter having a bisexual juvenile stage and being a rudimentary hermaphrodite. Acanthopagrus schlegelii is a protandric hermaphrodite. Standard length (LS ) at 50% sex change for A. schlegelii is 291 mm. LS at 50% female maturity for E. cardinalis and P. major are 117 and 332 mm, respectively. For all three species, the spawning period falls between November and March. The study highlights geographical differences in reproductive biology among the species and a paucity of fishery or other population-related data. While heavy fishing pressure, life-history characteristics and absence of effective management throughout the geographic ranges of these species make them susceptible to overfishing, they nonetheless appear to be generally more resilient than many other taxa that comprise the multi-species fisheries of the region, possibly due to their relatively rapid sexual maturation and spatial movement patterns. Overall, however, little is known of the biology, fishing history and current fishery status of sparids in general in the northern SCS and the current study is one of the first to examine such aspects of this family in the region and to consider appropriate management options.


Structural universality in disordered packings with size and shape polydispersity.
We numerically investigate disordered jammed packings with both size and shape polydispersity, using frictionless superellipsoidal particles. We implement the set Voronoi tessellation technique to evaluate the local specific volume, i.e., the ratio of cell volume over particle volume, for each individual particle. We focus on the average structural properties for different types of particles binned by their sizes and shapes. We generalize the basic observation that the larger particles are locally packed more densely than the smaller ones in a polydisperse-sized packing into systems with coupled particle shape dispersity. For this purpose, we define the normalized free volume vf to measure the local compactness of a particle and study its dependency on the normalized particle size A. The definition of vf relies on the calibrated monodisperse specific volume for a certain particle shape. For packings with shape dispersity, we apply the previously introduced concept of equivalent diameter for a non-spherical particle to define A properly. We consider three systems: (A) linear superposition states of mixed-shape packings, (B) merely polydisperse-sized packings, and (C) packings with coupled size and shape polydispersity. For (A), the packing is simply considered as a mixture of different subsystems corresponding to monodisperse packings for different shape components, leading to A = 1, and vf = 1 by definition. We propose a concise model to estimate the shape-dependent factor αc, which defines the equivalent diameter for a certain particle. For (B), vf collapses as a function of A, independent of specific particle shape and size polydispersity. Such structural universality is further validated by a mean-field approximation. For (C), we find that the master curve vf(A) is preserved when particles possess similar αc in a packing. Otherwise, the dispersity of αc among different particles causes the deviation from vf(A). These findings show that a polydisperse packing can be estimated as the combination of various building blocks, i.e., bin components, with a universal relation vf(A).


Paradoxical Reactions and the Immune Reconstitution Inflammatory Syndrome.
In HIV-infected individuals, paradoxical reactions after the initiation of antiretroviral therapy (ART) are associated with a variety of underlying infections and have been called the immune reconstitution inflammatory syndrome (IRIS). In cases of IRIS associated with tuberculosis (TB), two distinct patterns of disease are recognized: (i) the progression of subclinical TB to clinical disease after the initiation of ART, referred to as unmasking, and (ii) the progression or appearance of new clinical and/or radiographic disease in patients with previously recognized TB after the initiation of ART, the classic or "paradoxical" TB-IRIS. IRIS can potentially occur in all granulomatous diseases, not just infectious ones. All granulomatous diseases are thought to result from interplay of inflammatory cells and mediators. One of the inflammatory cells thought to be integral to the development of the granuloma is the CD4 T lymphocyte. Therefore, HIV-infected patients with noninfectious granulomatous diseases such as sarcoidosis may also develop IRIS reactions. Here, we describe IRIS in HIV-infected patients with TB and sarcoidosis and review the basic clinical and immunological aspects of these phenomena.


Catalytic Reduction of Carbon Dioxide on the (001), (011), and (111) Surfaces of TiC and ZrC: A Computational Study.
We present a computational study of the activity and selectivity of early transition-metal carbides as carbon dioxide reduction catalysts. We analyze the effects of the adsorption of CO2 and H2 on the (001), (011), and metal-terminated (111) surfaces of TiC and ZrC, as carbon dioxide undergoes either dissociation to CO or hydrogenation to COOH or HCOO. The relative stabilities of the three reduction intermediates and the activation energies for their formation allow the identification of favored pathways on each surface, which are examined as they lead to the release of CO, HCOOH, CH3OH, and CH4, thereby also characterizing the activity and selectivity of the two materials. Reaction energetics implicate HCO as the key common intermediate on all surfaces studied and rule out the release of formaldehyde. Surface hydroxylation is shown to be highly selective toward methane production as the formation of methanol is hindered on all surfaces by its barrierless conversion to CO.


Idiopathic reentrant right ventricular outflow tract tachycardia with presystolic potential of central pathway.
A 12-year-old girl with recurrent palpitation due to idiopathic ventricular tachycardia (VT) with a left bundle branch block configuration and inferior axis was referred to our hospital. During the VT, a spiky presystolic potential (SP) was recorded at the septum of right ventricular outflow tract (RVOT) just below pulmonary valve. The SP was entrained with a decremental property by pacing from right ventricular apex. Concealed entrainment was observed by pacing where the SP was recorded. Delivery of radiofrequency current targeting the SP abolished the VT. The SP with the decremental property could represent the central pathway of this idiopathic RVOT reentrant VT.


Fabricable concentric-ring metalens with high focusing efficiency based on two-dimensional subwavelength unit splicing.
To address the challenges posed by computational resource consumption and data volume in the development of large-aperture metalenses, a design method for concentric-ring metalens based on two-dimensional unit splicing is proposed in this paper. In the method, the unit structure library is constructed through global traversal under the machining process constraints. The phase matching is performed for two polarization states with specific weights and the design of binary-height, concentric-ring structures with arbitrary polarization sensitivity is realized, whose focusing efficiency (the encircled power within 3×FWHM of the focal spot divided by the near-field outgoing power) is up to 90%. Based on this method, a polarization-insensitive metalens with a design wavelength of 10µm, diameter of 2 cm, and numerical aperture of 0.447 is obtained. The method combines the advantages of lower computation requirements for a building block array of a metalens and lower structure data for a concentric-ring metalens. Consequently, it becomes possible to reduce calculation and processing costs by several orders of magnitude during the development process of metalenses with diameters ranging from 103 to 105 wavelengths. The resulting focusing efficiency can approach the upper limit achievable through global structural optimization and significantly surpass that of binary-height Fresnel lenses.


Effect of Noise on Time-frequency Analysis of Vibrocardiographic Signals.
Recordings of biological signals such as vibrocardiography often contain contaminating noise. Noise sources may include respiratory, gastrointestinal, and muscles movement, or environmental noise. Depending on individual physiology and sensor location, the vibrocardiographic (VCG) signals may be obscured by these noises in the time-frequency plane, which may interfere with automated characterization of VCG. In this study, polynomial chirplet transform (PCT) and smoothed pseudo Wigner-Ville distribution (SPWVD) were used to estimate the instantaneous frequency (IF) of two simulated VCG signals. One simulated signal contained a time-varying IF while the other had a fixed IF. The error in estimating IF was then calculated for signal-to-noise ratios (SNR) from -10 to 10 dB. Analysis was repeated 100 times at each level of noise using randomized sets of white noise. Error analysis showed that the range of errors in estimating IF was wider when SNR decreased. Results also showed that PCT tended to outperform SPWVD at high SNR. For example, PCT was more accurate at SNR > 3 dB for a simulated VCG signal with constant frequency components, at SNR>-10 dB for a simulated VCG signal with time-varying frequency, and at SNR > 0 for an actual VCG.


Oxidation of cysteinesulfinic acid by hexachloroiridate(IV).
We report the results of an experimental study of the oxidation of cysteinesulfinic acid (CysSO2H) by [IrCl6](2-) in aqueous media at 25 °C in order to gain insight into the mechanisms of oxidation of alkylsulfinic acids by simple one-electron oxidants. When the reaction is performed with exclusion of O2 between pH 3 and 5, it is complete in several seconds. The products are [IrCl6](3-) and CysSO3H. Kinetic data obtained by stopped-flow UV-vis methods with [CysSO2H] ≫ [Ir(IV)]0 reveal the rate law to be -d[Ir(IV)]/dt = k[Ir(IV)](2)[CysSO2H]/[Ir(III)] with a negligible pH dependence. The value of k is (6.8 ± 0.12) × 10(3) M(-1) s(-1) at μ = 0.1 M (NaClO4). A mechanism is inferred in which the first step is a rapid and reversible electron-transfer equilibrium between Ir(IV) and CysSO2(-) to form Ir(III) and CysSO2(•). The second step is the rate-limiting inner-sphere oxidation of CysSO2(•) by Ir(IV). Production of CysSO3H is proposed to occur through hydrolysis of an Ir(III)-bound sulfonyl chloride that is the immediate product of the inner-sphere second step.


A physiotherapy-led review of guideline-based care for community-dwelling older people presenting to a metropolitan hospital with accidental falls.
Several guidelines exist to inform best-practice management of community-dwelling fallers. This study aimed to outline a pragmatic approach to developing an audit tool for guideline-based care of falls and provide an overview of current practice. An audit tool to determine compliance with guideline-based care was developed with an allied health and physiotherapy focus, utilising the Australian Commission on Safety and Quality in Health-Care Guidelines for Preventing Falls and Harm from Falls in Older People (2009) and Queensland State Government 'Stay on your Feet' guidelines. A retrospective audit of medical records was completed in July 2020 of community-dwelling people aged 65 years and over with a fall-related emergency department (ED) presentation in a medium-sized metropolitan hospital in Australia. Data were compared between patients admitted to hospital and those discharged home from the ED. Ninety-three patients were included: 68 were discharged home from ED and 25 were admitted to hospital. There was a significant difference in receiving an allied health review (p < .001) between admitted patients (96%) and those who discharged home from ED (68%). The Clinical Frailty Scale was only completed for 23% of patients. Physiotherapy quality-of-care (n = 46 patients) was variable, with poor completion of physical outcome measures (7%) and fall education (4%). However, assessment of mobility was routinely completed (94%), and most patients were referred to an appropriate community service (66%). Adherence to guideline-based care of community-dwelling fallers is inconsistent. Improvements are required in the consistency of risk stratification, comprehensive physical assessment and patient education.


Unusual evolution of a superoxide dismutase-like gene from the extremely halophilic archaebacterium Halobacterium cutirubrum.
The archaebacterium Halobacterium cutirubrum contains a single detectable, Mn-containing superoxide dismutase, which is encoded by the sod gene (B. P. May and P. P. Dennis, J. Biol. Chem. 264:12253-12258, 1989). The genome of H. cutirubrum also contains a closely related sod-like gene (slg) of unknown function that has a pattern of expression different from that of sod. The four amino acid residues that bind the Mn atom are conserved, but the flanking regions of the two genes are unrelated. Although the genes have 87% nucleotide sequence identity, the proteins they encode have only 83% amino acid sequence identity. Mutations occur randomly at the first, second, and third codon positions, and transversions outnumber transitions. Most of the mutational differences between the two genes are confined to two limited regions; other regions totally lack differences. These two gene sequences are apparently in the initial stage of divergent evolution. Presumably, this divergence is being driven by strong selection at the molecular level for either acquisition of new functions or partition and refinement of ancestral functions in one or both of the respective gene products.


The Effect of Sacubitril/Valsartan Treatment on Cardiac and Renal Functions of a Patient With Cardiorenal Syndrome Type 4 and Stage 5 CKD After More Than Three Years of Follow-Up.
It is difficult to treat cardiorenal syndrome (CRS) in clinical practice, which is the common reason for the death of patients. This report aimed to describe the effects of sacubitril/valsartan treatment on cardiac and renal functions of a patient with cardiorenal syndrome type 4 (CRS4) after more than 3 years of follow-up. A 77-year-old Chinese woman was admitted to our hospital because of CRS4 and stage 5 chronic kidney disease (CKD), who had a history of long-term proteinuria and renal failure. The patient's cardiothoracic ratio (CTR) measured by chest X-ray was 0.6. Cardiac ultrasonography showed that the left ventricular ejection fraction (LVEF) was 0.40. The patient had been treated for heart failure (HF) for 5 months, but there was no improvement in clinical manifestations, and the renal function gradually deteriorated. In our hospital, she received sacubitril/valsartan treatment for at least 40 months. The symptoms of HF relieved, and the indices of cardiac function improved. In addition, the patient's renal function was stable. During the treatment, the dosage of sacubitril/valsartan needed to be adjusted to achieve the optimal therapeutic effect. Follow-up results showed that she achieved cardiac function of New York Heart Association (NYHA) class II with an ejection fraction of 0.60 and E/A > 1 indicated by echocardiogram, and did not develop hyperkalemia. In summary, the improvement of cardiac and renal functions of the CRS4 patient was associated with the long-term sacubitril/valsartan treatment.


Posttranslational regulation of tissue inhibitor of metalloproteinase-1 by calcium-dependent vesicular exocytosis.
Liver myofibroblasts derived from hepatic stellate cells (HSC) are critical mediators of liver fibrosis. Release of tissue inhibitor of metalloproteinase-1 (TIMP-1) advances liver fibrosis by blocking fibrinolysis. The mechanisms responsible for the posttranslational regulation of TIMP-1 by myofibroblastic HSC are unknown. Here, we demonstrate that TIMP-1 release by HSC is regulated in a posttranslational fashion via calcium-sensitive vesicular exocytosis. To our knowledge, this is the first article to directly examine vesicular trafficking in myofibroblastic HSC, potentially providing a new target to treat and or prevent liver fibrosis.


Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity.
Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4(HC-/-) mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4(HC-/-) mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.


Anaphylactic shock decreases cerebral blood flow more than what would be expected from severe arterial hypotension.
The effects of acute reduction in arterial blood pressure in severe anaphylactic shock (AS) on cerebral blood flow are of paramount importance to be investigated. We studied cerebral circulation and oxygenation in a model of severe AS and compared it with a pharmacologically induced arterial hypotension of similar magnitude. Anaphylactic shock was induced by 1 mg intravenous ovalbumin (OVA) in sensitized rats. Rats were randomized to three groups: (i) no resuscitation (OVA; n = 10) (ii) intravenous volume expansion (10 mL in 10 min after OVA injection) (OVA + VE; n = 10); (iii) control hypotension (100 μg of nicardipine followed by continuous infusion of 1 mg · 100 g · h intravenously; NICAR; n = 10). Mean arterial pressure (MAP), carotid blood flow (CBF), cardiac output, cerebral cortical blood flow (CCBF; estimated by laser Doppler technique), and cerebral tissue oxygen pressure (PtiO2) were recorded over the 15 min following AS induction in all three groups. Results are expressed as mean (SD). One minute after OVA or nicardipine injection, there was a rapid and significant 50% decrease in MAP from basal values. In the OVA group, AS severely altered systemic and cerebral hemodynamics in 5 min: 93% (SD, 4%) decrease in CBF, 66% (SD, 8%) in CCBF, and 44% (SD, 8%) in PtiO2; the decrease in CBF was significantly (P < 0.05) attenuated in the OVA + VE group; however, CCBF and PtiO2 were not statistically different in the OVA versus OVA + VE groups. On the contrary, nicardipine-induced hypotension had only a limited impact on CBF, cardiac output, CCBF, and PtiO2 for a similar MAP decrease. There was a linear relation between CCBF and blood pressure in the OVA (regression slope: 0.87 [SD, 0.06]; median r = 0.81) but not in the NICAR group (regression slope: 0.23 [SD, 0.32]; median r = 0.33). Anaphylactic shock resulted in severe impairment of cerebral blood flow and oxygenation, beyond what could be expected from the level of arterial hypotension.


Detection of let-7 miRNAs in urine supernatant as potential diagnostic approach in non-metastatic clear-cell renal cell carcinoma.
Urinary microRNAs (miRNAs) are emerging as a clinically useful tool for early and non-invasive detection of various types of cancer. The aim of this study was to evaluate whether let-7 family miRNAs differ in their urinary concentrations between renal cell carcinoma (RCC) cases and healthy controls. In the case-control study, 69 non-metastatic clear-cell RCC patients and 36 gender/age-matched healthy controls were prospectively enrolled. Total RNA was purified from cell-free supernatant of the 105 first morning urine specimens. Let-7 family miRNAs were determined in cell-free supernatant using quantitative miRNA real-time reverse-transcription PCR and absolute quantification approach. Concentrations of all let-7 miRNAs (let-7a, let-7b, let-7c, let-7d, let-7e and let-7g) were significantly higher in urine samples obtained from RCC patients compared to healthy controls (P < 0.001; P < 0.001; P = 0.005; P = 0.006; P = 0.015 and P = 0.002, respectively). Subsequent ROC analysis has shown that let-7a concentration possesses good ability to differentiate between cases and controls with area under curve being 0.8307 (sensitivity 71%, specificity 81%). We have shown that let-7 miRNAs are abundant in the urine samples of patients with clear-cell RCC, and out of six let-7 family members, let-7a outperforms the others and presents promising non-invasive biomarker for the detection of RCC.


Early steroid pulse therapy for children with suspected acute encephalopathy: An observational study.
Steroid pulse therapy is widely used to treat virus-associated acute encephalopathy, especially the cytokine storm type; however, its effectiveness remains unknown. We sought to investigate the effectiveness of early steroid pulse therapy for suspected acute encephalopathy in the presence of elevated aspartate aminotransferase (AST) levels.We enrolled children admitted to Hyogo Children's Hospital between 2003 and 2017 with convulsions or impaired consciousness accompanied by fever (temperature >38°C). The inclusion criteria were: refractory status epilepticus or prolonged neurological abnormality or hemiplegia at 6 hours from onset, and AST elevation >90 IU/L within 6 hours of onset. We excluded patients with a neurological history. We compared the prognosis between the groups with or without steroid pulse therapy within 24 hours. A good prognosis was defined as a Pediatric Cerebral Performance Category Scale (PCPC) score of 1-2 at the last evaluation, within 30 months of onset. Moreover, we analyzed the relationship between prognosis and time from onset to steroid pulse therapy.Fifteen patients with acute encephalopathy and 5 patients with febrile seizures were included in this study. Thirteen patients received steroid pulse therapy within 24 hours. There was no between-group difference in the proportion with a good prognosis. There was no significant correlation between PCPC and timing of steroid pulse therapy (rs = 0.253, P = .405). Even after excluding 2 patients with brainstem lesions, no significant correlation between PCPC and steroid pulse therapy timing (rs = 0.583, P = .060) was noted. However, the prognosis tended to be better in patients who received steroid pulse therapy earlier.Steroid pulse therapy within 24 hours did not improve the prognosis in children with suspected acute encephalopathy associated with elevated AST. Still, even earlier administration of treatment could prevent the possible neurological sequelae of this condition.


Evaluating the effectiveness of a 'Tobacco Monitor' App in reporting violations of tobacco policy in the community.
It is of interest to evaluate the effectiveness of the "Tobacco Monitor" app in reporting violations of tobacco policy in the community. Hence, a study was conducted amongst the first and second-year undergraduate students of health science colleges of a University. Students were asked to register complaints related to tobacco violations on the tobacco monitor app. Registered complaints were verified by the National Forum for Tobacco Eradication (NFTE) and descriptive statistics were used in reporting the results. A total of 208 complaints on tobacco violation were registered through the Tobacco Monitor app, 163 valid complaints were identified and 45 reports were found invalid. 163 verified valid complaints by NFTE were transferred to the Non-Communicable Diseases (NCD) Cell, Maharashtra, India. It should be noted that anti-tobacco laws and national policies help to curb the menace of the tobacco epidemic to an extent. However, robust reporting and sustainable enforcement measures are required in implementing tobacco legislation effectively. We also report that youth are comfortable in using the Tobacco Monitor app for reporting violations on tobacco.


[Change in ghrelin level with the amelioration of glucose and lipid metabolic disorder in OLETF rats].
To explore the exact role of ghrelin in glyco- and lipo-metabolism. We compared the levels of ghrelin mRNA in gastric tissue, ghrelin in gastric tissue and plasma among LETO rats( non diabetes, n=10), OLETF rats( type 2 diabetes, n=10), OLETF/M rats( OLETF rats managed with Metformin at the dose of 100 mg/kg weight, n=10) and OLETF/F rats( OLETF rats managed with Fenofibrate at the dose of 20 mg/kg weight, n=10). The levels of ghrelin mRNA were tested by Northern blotting, and the ghrelin content in gastric tissue and plasma detected by RIA. At the age of 30 weeks, the ghrelin fasting plasma levels of OLETF rats were lower than those of LETO rats(37.49+/-6.42 vs 58.52+/-5.85, P<0.05). The fasting blood plasma ghrelin levels of OLETF/M groups showed an increased tendency, but the difference of the fasting blood plasma ghrelin levels to those of the untreated OLETF rats were not noticeable(49.65+/-6.76 vs 37.49+/-6.42,P>0.05). However, the fasting blood plasma ghrelin levels of OLETF/F group were more than those that of the untreated OLETF rats (62.02+/-7.35 vs 37.49+/- 6.42,P<0.05). The mRNA and polypeptide levels of ghrelin in stomach tissue had no marked difference in the 4 groups at the age of 17 weeks. At the age of 30 weeks, the difference of mRNA(1.18+/-0.06 vs 1.27+/-0.05,P<0.05) and polypeptide (114.77+/- 31.65 vs 152.87+/-18.24, P<0.05) between OLETF group and LETO group had been observed. Metformin didn't influence the mRNA and polypeptide levels of ghrelin in stomach tissue markedly. Howere, the polypeptide (161.75+/-23.61 vs 114.77+/-31.65, P<0.05) and mRNA(1.36+/-0.09 vs 1.18+/-0.06,P<0.05) levels of ghrelin in stomach tissue of OLETF/F group were markedly higher than those of stomach tissue ghrelin in the untreated OLETF group. Our data demonstrate that ghrelin may play a role in protective, compensative and negative-feedback regulation in the disorder of glucose and lipid metabolism.


Quantitative relationship between myocardial concentration of tacrolimus and QT prolongation in guinea pigs: pharmacokinetic/pharmacodynamic model incorporating a site of adverse effect.
Clinical cases have been reported of tacrolimus (FK506)-induced QT prolongation. We have previously demonstrated sustained QT prolongation by FK506 in guinea pigs. Herein, we aimed to conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis of FK506, using a model involving the myocardial compartment. The pharmacokinetics of FK506 and its effects on QTc intervals were investigated in guinea pigs. In the pharmacokinetic study, whole blood and ventricular FK506 concentrations were analyzed, using a 4-compartment model during and after intravenous infusion of FK506 (0.01 or 0.1 mg/hr/kg). Subsequently, the concentration-response relationship between ventricular FK506 concentration and change in QTc interval was analyzed, using the maximal effect (Emax) model. Pharmacokinetic profiles of FK506 showed a delayed distribution of FK506 into the ventricle. Furthermore, the observed QT prolongation paralleled the ventricular FK506 concentrations, with no lag-time between the two. The Emax model successfully described the relationship between changes in QTc interval and ventricular FK506 concentrations. In conclusion, the PK/PD model where the myocardial drug concentration of FK506 was linked with its adverse effect could describe, for the first time, the anti-clockwise hysteresis observed in the relationship between blood FK506 concentration and QTprolongation. Such a hysteresis pattern for QTprolongation might be caused, therefore, mainly by the delayed disposition of FK506 to ventricular myocytes.


Contribution of HIV-1 genomes that do not integrate to the basic reproductive ratio of the virus.
Recent experimental data indicate that HIV-1 DNA that fails to integrate (from now on called uDNA) can by itself successfully produce infectious offspring virions in resting T cells that become activated after infection. This scenario is likely important at the initial stages of the infection. We use mathematical models to calculate the relative contribution of unintegrated and integrated viral DNA to the basic reproductive ratio of the virus, R0, and the models are parameterized with preliminary data. This is done in the context of both free virus spread and transmission of the virus through virological synapses. For free virus transmission, we find that under preliminary parameter estimates, uDNA might contribute about 20% to the total R0. This requires that a single copy of uDNA can successfully replicate. If the presence of more than one uDNA copy is required for replication, uDNA does not contribute to R0. For synaptic transmission, uDNA can contribute to R0 regardless of the number of uDNA copies required for replication. The larger the number of viruses that are successfully transmitted per synapse, however, the lower the contribution of uDNA to R0 because this increases the chances that at least one virus integrates. Using available parameter values, uDNA can maximally contribute 20% to R0 in this case. We argue that the contribution of uDNA to virus reproduction might also be important for continued low level replication of HIV-1 in the presence of integrase inhibitor therapy. Assuming a 20% contribution of uDNA to the overall R0, our calculations suggest that R0=1.6 in the absence of virus integration. While these are rough estimates based on preliminary data that are currently available, this analysis provides a framework for future experimental work which should directly measure key parameters.


The influence of hyperoxia on cough reflex intensity in guinea pigs treated with bleomycin.
Inhalation of high concentration of oxygen produces a lung injury in men and experimental animals. In our previous experiment we have found suppression of cough reflex in healthy guinea pigs after an exposure to 100% O2 for 60 hours. This study was designed to find the effect of hyperoxia on cough reflex in guinea pigs with lungs damaged by bleomycin. We used 48 animals (300-400 g) in two separated experiments. 32 of them were intratracheally injected with 1.5 mg bleomycin (Bleocin, Nippon Kayaku Co., Ltd., Tokyo, Japan) for induction of lung damage according to the method described by Parizada et al (20). 16 animals were given saline, only (control). Animals of experimental group were divided into two subgroups according to the lapse of time from bleomycin application. 13 days after bleomycin application animals of the 1st subgroup (16) were exposed to 100% O2 (8) or to room air (8) for 48 h. Similarly, 20 days after bleomycin application guinea pigs of the 2nd subgroup (16) were exposed to 100% O2 (8) or air (8), respectively. Cough was provoked in conscious animals placed in bodyplethysmograph box by inhalation of citric acid aerosol (0.3 mol/L) before, then 13 or 20 days after bleomycin application, and finally at the end of 48-h exposition to 100% O2 (air). The number of coughs was counted from airflow trace recorded by pneumotachograph. Cough was also induced by mechanical stimulation of laryngopharyngeal (LPh) and tracheobronchial (TBr) region in anaesthetized animals (Urethane, 1.1 g/kg, i.p.) just after the end of oxygen exposition and was evaluated from the interpleural pressure record. The results have shown a tendency to inhibition of citric acid cough reflex in animals 13 days treated with bleomycin and exposed to 100% O2, and significant decrease in citric acid induced cough in animals 20 days treated with bleomycin and exposed to 100% O2. Significant changes were present in cough intensity induced by mechanical stimulation of TBr region of the guinea pigs airway treated with bleomycin and exposed to oxygen, too. (Tab. 1, Fig. 3, Ref: 29.)


A rare cause of postpartum low back pain: pregnancy- and lactation-associated osteoporosis.
Pregnancy- and lactation-associated osteoporosis (PLO) is a rare form of osteoporosis. It results in severe low back pain in the last trimester of pregnancy and in the postpartum period, decreases in height, and fragility fractures, particularly in the vertebra. The current case report presents a 32-year-old patient who presented with back and low back pain that began in the last trimester of the pregnancy and worsened at two months postpartum and who was diagnosed with pregnancy- and lactation-associated osteoporosis after exclusion of other causes; the findings are discussed in view of the current literature. PLO is a rare clinical condition causing significant disability. PLO must be kept in mind in the differential diagnosis in patients presenting with low back pain during or after pregnancy. The patients must be evaluated for the risk factors of PLO, and an appropriate therapy must be initiated.


Do hormones cause breast cancer?
The evidence that various endogenous and exogenous sex hormones play a role in the etiology of breast cancer is reviewed. It is hypothesized that prolonged exposure to normal levels of ovarian estrogens and cyclic progesterone resulting from early menarche and late menopause, and primarily willful nulliparity and late childbearing, act at an early stage in the development of breast cancer by promoting excessive proliferation of normal epithelial stem cells. Excess endogenous or exogenous estrogens can enhance risk by stimulating proliferation of epithelial cells that have undergone partial malignant transformation. The breast, however, is much less responsive to the tumor-promoting effects of estrogens than the endometrium, and estrogens probably play a less important role in the later stages of mammary than endometrial carcinogenesis.


MicroRNA-26a regulates ANXA1, rather than DAL-1, in the development of lung cancer.
The aim of the present study was to investigate the expression and role of microRNA-26a (miR-26a) in lung cancer, and to verify whether differentially expressed in adenocarcinoma of the lung (DAL-1) is the target protein of miR-26a. mRNA expression levels of miR-26a and DAL-1 were detected using reverse transcription-quantitative polymerase chain reaction. Protein expression levels of DAL-1 and annexin A1 (ANXA1) were evaluated by western blot analysis. Cell Counting Kit-8, Transwell and wound scratch healing assays were used to characterize the function of miR-26a in lung cancer cells. The association of DAL-1 with miR-26a or ANXA1 was determined by dual-luciferase reporter or two-dimensional gel electrophoresis assays. miR-26a revealed decreased expression levels in lung cancer tissues compared with normal lung tissues, and decreased expression levels in lung cancer cells compared with 16HBE cells. Inhibition of miR-26a promoted lung cancer cell growth, migration and invasion. The DAL-1 protein exhibited downregulated expression levels in lung cancer tissues. DAL-1 was not the direct target gene of miR-26a. The two-dimensional gel electrophoresis assay confirmed that DAL-1 and ANXA1 were associated proteins. Expression levels of the ANXA1 protein were increased following DAL-1 gene silencing. The altered expression level of miR-26a affected the expression of ANXA1, and not of DAL-1. miR-26a demonstrated decreased expression levels in lung cancer cells, and it has an important effect on the biological function of lung cancer cells. However, DAL-1 was not a target gene of miR-26a. As a DAL-1 associated protein, ANXA1 was regulated by miR-26a.


Report of 121 Cases of Bell's Palsy Referred to the Emergency Department.
According to the high incidence of Bell's palsy (IFP) and lack of clinical data regarding different aspects of disease, the present study investigated 121 Iranian patients with peripheral facial paralysis referred to the emergency department. In this retrospective study, all patients with peripheral facial paralysis, referred to the emergency department of Poursina hospital, Rasht, Iran, from August 2012 to August 2013, were enrolled. For all patients with diagnosis of Bell's palsy variables such as age, sex, occupation, clinical symptoms, comorbid disease, grade of paralysis, and the severity of the facial palsy were reviewed and analyzed using STATA version 11.0. 121 patients with peripheral facial paralysis were assessed with a mean age of 47.14±18.45 years (52.9% male). The majority of patients were observed in the summer (37.2%) and autumn (33.1%) and the recurrence rate was 22.3%. The most common grades of nerve damage were IV and V based on House-Brackman grading scale (47.1%). Also, the most frequent signs and symptoms were ear pain (43.8%), taste disturbance (38.8%), hyperacusis (15.7%) and increased tearing (11.6%). There were not significant correlations between the severity of palsy with age (p= 0.08), recurrence rate (p=0.18), season (p=0.9), and comorbid disease including hypertension (p=0.18), diabetes (p=0.29), and hyperlipidemia (p=0.94). The patients with any of following symptoms such as ear pain (p<0.001), taste disturbance (p<0.001), increased tearing (p=0.03), and Hyperacusis (p<0.001) have more severe palsy. There was equal gender and occupational distribution, higher incidence in fourth decade of life, higher incidence in summer and autumn, higher grade of nerve damage (grade V and VI), and higher incidence of ear pain and taste disturbance in patients suffered from IFP. In addition, there was significant association between severity of nerve damage and presence of any simultaneous symptoms.


Do not attempt cardiopulmonary resuscitation decisions: joint guidance.
Since its introduction in the 1960s as a treatment to restart the heart after sudden cardiac arrest from a heart attack, attempts at cardiopulmonary resuscitation have become more common in other clinical situations. Cardiopulmonary resuscitation can be a lifesaving treatment, with the likelihood of recovery varying greatly depending on individual circumstances; however, overall, the proportion of people who survive following cardiopulmonary resuscitation is relatively low. Anticipatory decisions were recognised as being the best way of ensuring that cardiopulmonary resuscitation was not attempted against individuals' wishes. Since 2001, the British Medical Association, Resuscitation Council (UK) and Royal College of Nursing have published professional guidance on decisions relating to cardiopulmonary resuscitation. The latest version of this guidance was published in June 2016. This paper summarises the key legal and ethical principles that should inform all cardiopulmonary resuscitation decisions, with particular emphasis on the recent changes in law and policy.


Experience with caspofungin in the treatment of persistent fungemia in neonates.
To review our experience of caspofungin in the treatment of persistent candidemia in the neonatal intensive care unit. This was a retrospective chart review on 13 infants in whom caspofungin was added to conventional antifungals (amphotericin B and/or fluconazole or flucytosine) for the treatment of refractory candidemia. A total of 12 infants were preterm (gestational age, 24 to 28 weeks) and one was term; the median birth weight was 800 g (range, 530 to 5600 g). Candidemia (Candida albicans in five, C. parapsilosis in six, C. albicans and C. parapsilosis in one and C. tropicalis in one) persisted despite 6 to 30 days of conventional antifungal therapy. After the addition of caspofungin, sterilization of blood cultures was achieved in 11 infants at the median time of 3 days (range, 1 to 21 days). Adverse events included thrombophlebitis (one patient), hypokalemia (two patients) and elevation of liver enzymes (four patients). Three infants had a second episode of candidemia and seven patients died. Caspofungin may be an efficacious addition for treatment of candidemia refractory to conventional antifungal therapy. This drug should be further investigated in neonates.


Natural attack rate of influenza in unvaccinated children and adults: a meta-regression analysis.
The natural (i.e. unvaccinated population) attack rate of an infectious disease is an important parameter required for understanding disease transmission. As such, it is an input parameter in infectious disease mathematical models. Influenza is an infectious disease that poses a major health concern worldwide and the natural attack rate of this disease is crucial in determining the effectiveness and cost-effectiveness of public health interventions and informing surveillance program design. We estimated age-stratified, strain-specific natural attack rates of laboratory-confirmed influenza in unvaccinated individuals. Utilizing an existing systematic review, we calculated the attack rates in the trial placebo arms using a random effects model and a meta-regression analysis (GSK study identifier: 117102). This post-hoc analysis included 34 RCTs (Randomized Control Trials) contributing to 47 influenza seasons from 1970 to 2009. Meta-regression analyses showed that age and type of influenza were important covariates. The attack rates (95% CI (Confidence Interval)) in adults for all influenza, type A and type B were 3.50% (2.30%, 4.60%), 2.32% (1.47%, 3.17%) and 0.59% (0.28%, 0.91%) respectively. For children, they were 15.20% (11.40%, 18.90%), 12.27% (8.56%, 15.97%) and 5.50% (3.49%, 7.51%) respectively. This analysis demonstrated that unvaccinated children have considerably higher exposure risk than adults and influenza A can cause more disease than influenza B. Moreover, a higher ratio of influenza B:A in children than adults was observed. This study provides a new, stratified and up to-date natural attack rates that can be used in influenza infectious disease models and are consistent with previous published work in the field.


Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens III. Appropriate follow-up testing in vivo.
There has been much discussion in recent years regarding the most appropriate follow-up testing in vivo when positive results are obtained in vitro but the in vivo micronucleus (MN) test (traditionally the most widely-used test) is negative. Not all rodent carcinogens give positive results in the micronucleus test, and so it has been common practice to include a second in vivo assay such as the unscheduled DNA synthesis (UDS) test. This has proved useful but is usually limited to analysis of rodent (usually rat) liver. With the increased evaluation and use of other in vivo assays, e.g. for transgenic mutations (TG) and DNA damage (Comet assay) it was important to investigate their usefulness. We therefore examined the published in vivo UDS, TG and Comet-assay results for 67 carcinogens that were negative or equivocal in the micronucleus test. Between 30 and 41 chemicals were evaluated in each of the three in vivo tests, with some overlap. In general, the UDS test was disappointing and gave positive results with <20% of these carcinogens, some of which induced tumours in rat liver and produced DNA adducts in vivo. The TG assay gave positive responses with >50% of the carcinogens, but the Comet assay detected almost 90% of the micronucleus-negative or equivocal carcinogens. This pattern of results was virtually unchanged when the in vitro profile (gene mutagen or clastogen) was taken into account. High sensitivity (ability to detect carcinogens as positive) is only really useful when the specificity (ability to give negative results with non-carcinogens) is also high. Based on small numbers of publications with non-carcinogens, the TG and Comet assays gave negative results with non-carcinogens on 69 and 78% of occasions, respectively. Although further evaluation of the Comet and TG assays, particularly with non-carcinogens, is needed, these data suggest that they both should play a more prominent role in regulatory testing strategies than the UDS test.


Diagnostic value of plasma renin activity and plasma angiotensin II in renovascular hypertension.
The plasma renin activity in both peripheral venous blood and the renal vein of the involved kidney showed high values. Angiotensin infusion elevated the urine volume and angiotensin excretion on the intact side, and the difference in urine volume and angiotensin excretion between the two sides was accentuated after angiotensin infusion. These findings are useful for the diagnosis of the stenotic side in renovascular hypertension. No difference in the prognosis of extirpation of the involved kidney and of vascular reconstruction of the stenotic artery was found for the treatment of renovascular hypertension. However, autotransplantation of the involved kidney was found to be more useful, since it allowed improvement of renal circulation, suppression of thrombosis formation, and the maintenance of kidney tissue.


Of vigilance and invisibility--being a patient in technologically intense environments.
Equipment and procedures developed during the past several decades have made the modern intensive care unit (ICU) the hospital's most technologically advanced environment. In terms of patient care, are these advances unmitigated gains? This study aimed to develop a knowledge base of what it means to be critically ill or injured and cared for in technologically intense environments. A lifeworld perspective guided the investigation. Nine unstructured interviews with intensive care patients comprise its data. The qualitative picture uncovered by a phenomenological analysis shows that contradiction and ambivalence characterized the entire care episode. The threat of death overshadows everything and perforates the patient's existence. Four inter-related constituents further elucidated the patients' experiences: the confrontation with death, the encounter with forced dependency, an incomprehensible environment and the ambiguity of being an object of clinical vigilance but invisible at the personal level. Neglect of these issues lead to alienating 'moments' that compromised care. Fixed at the end of a one-eyed clinical gaze, patients described feeling marginalized, subjected to rituals of power, a stranger cared for by a stranger. The roar of technology silences the shifting needs of ill people, muffles the whispers of death and compromises the competence of the caregivers. This study challenges today's caregiving system to develop double vision that would balance clinical competence with a holistic, integrated and comprehensive approach to care. Under such vision, subjectivity and objectivity would be equally honoured, and the broken bonds re-forged between techne, 'the act of nursing', and poesis, 'the art of nursing'.


Electro-acupuncture Promotes Angiogenesis via Exosomal miR-210 in the Hypoxia-induced HUVECs Mediated HIF-1α/VEGF/Notch 1 Signal Pathway.
Acupuncture has been wildly applied for cerebral ischemia treatment in China for thousands of years, while the specific mechanism remains uncertain. Recently, many studies have shown that acupuncture promotes angiogenesis after ischemia occurs. Here, we examined the effect of electro-acupuncture (EA) exosomes on angiogenesis in hypoxia-induced human umbilical vein endothelial cells (HUVECs). To investigate whether EA exosomal miR-210 promotes angiogenesis in the hypoxiainduced HUVECs via the HIF-1α/VEGF/Notch 1 signal pathway. The middle cerebral artery occlusion (MCAO) model was established and treated with EA therapy. Then, exosomes were identified and isolated from rats' plasma in the MCAO+EA group by transmission electron microscopy (TEM), surface markers expressions, and PKH26 reagent. MiR- 210 mimic, miR-210 inhibitor, and HIF-1α were transfected. Flow cytometry, CCK-8 assay, and Transwell assay were conducted to assess the migration, apoptosis, and proliferation of each group of cells. Western blot and quantitative PCR were performed to detect the CD34, HIF-1α, VEGF, Notch 1, and miR-210 expression levels in each group. MiR-210 was significantly upregulated in exosomes of the MCAO plasma, and further enhanced by EA therapy. EA-EXOs and miR-210 mimic inhibited cell apoptosis, promoted cell proliferation and cell migration in hypoxia-induced HUVECs. However, the miR-210 inhibitor reversed the proliferation and migration number induced by EA-EXOs. Besides, EA-EXOs and miR- 210 mimic further enhanced those HIF-1α, VEGF, and Notch 1 levels compared to the hypoxia treatment only. Silencing HIF-1α or miR-210 reversed the high expressions of those three angiogenic factors induced by hypoxia and EA-EXO. qPCR showed similar trends with their relative mRNAs. To analyze these associations quantificationally, Spearman's rank correlation coefficient was calculated. As revealed by results, the expression of proteins and mRNA were highly correlative with each other. These results indicated that EA-EXO miR-210 promotes angiogenesis in hypoxia conditions via HIF-1α/VEGF/Notch 1 signal pathway.


Solubility and distribution of halothane in human blood.
The interactions of halothane with five major constituents of human blood were studied by equilibrium dialysis. Haemoglobin, albumin, red cell membranes and triglycerides were found to contribute significantly to the solubility, and thus the transport, of halothane in whole blood. At physiological concentrations, gamma-globulin had no detectable effect on the solubility of halothane. Absorption isotherms of halothane binding to haemoglobin and albumin suggest a possible positive co-operative effect, but complete saturation of the binding sites was not observed even when the aqueous phase was saturated with halothane. The number of halothane molecules bound per albumin molecule was not significantly affected by the presence of oleic acid. For red cell ghosts and triglyceride-rich micelles (chylomicrons and very low density lipoprotein), the adsorption isotherms suggested that halothane is solubilized within the hydrophobic regions. The distribution of halothane between cells and plasma calculated from the above equilibrium dialysis results was in reasonable agreement with the distribution in whole blood determined by an independent method.


The effect of framing and normative messages in building support for climate policies.
Deep cuts in greenhouse gas emissions are required to mitigate climate change. However, there is low willingness amongst the public to prioritise climate policies for reducing emissions. Here we show that the extent to which Australians are prepared to reduce their country's CO2 emissions is greater when the costs to future national income are framed as a "foregone-gain"--incomes rise in the future but not by as much as in the absence of emission cuts--rather than as a "loss"--incomes decrease relative to the baseline expected future levels (Studies 1 & 2). The provision of a normative message identifying Australia as one of the world's largest CO2 emitters did not increase the amount by which individuals were prepared to reduce emissions (Study 1), whereas a normative message revealing the emission policy preferences of other Australians did (Study 2). The results suggest that framing the costs of reducing emissions as a smaller increase in future income and communicating normative information about others' emission policy preferences are effective methods for leveraging public support for emission cuts.


Benchmarking to Identify Practice Variation in Test Ordering: A Potential Tool for Utilization Management.
Appropriate test utilization is usually evaluated by adherence to published guidelines. In many cases, medical guidelines are not available. Benchmarking has been proposed as a method to identify practice variations that may represent inappropriate testing. This study investigated the use of benchmarking to identify sites with inappropriate utilization of testing for a particular analyte. We used a Web-based survey to compare 2 measures of vitamin D utilization: overall testing intensity (ratio of total vitamin D orders to blood-count orders) and relative testing intensity (ratio of 1,25(OH)2D to 25(OH)D test orders). A total of 81 facilities contributed data. The average overall testing intensity index was 0.165, or approximately 1 vitamin D test for every 6 blood-count tests. The average relative testing intensity index was 0.055, or one 1,25(OH)2D test for every 18 of the 25(OH)D tests. Both indexes varied considerably. Benchmarking can be used as a screening tool to identify outliers that may be associated with inappropriate test utilization.


Personalizing Cancer Pain Therapy: Insights from the Rational Use of Analgesics (RUA) Group.
A previous Delphi survey from the Rational Use of Analgesics (RUA) project involving Italian palliative care specialists revealed some discrepancies between current guidelines and clinical practice with a lack of consensus on items regarding the use of strong opioids in treating cancer pain. Those results represented the basis for a new Delphi study addressing a better approach to pain treatment in patients with cancer. The study consisted of a two-round multidisciplinary Delphi study. Specialists rated their agreement with a set of 17 statements using a 5-point Likert scale (0 = totally disagree and 4 = totally agree). Consensus on a statement was achieved if the median consensus score (MCS) (expressed as value at which at least 50% of participants agreed) was at least 4 and the interquartile range (IQR) was 3-4. This survey included input from 186 palliative care specialists representing all Italian territory. Consensus was reached on seven statements. More than 70% of participants agreed with the use of low dose of strong opioids in moderate pain treatment and valued transdermal route as an effective option when the oral route is not available. There was strong consensus on the importance of knowing opioid pharmacokinetics for therapy personalization and on identifying immediate-release opioids as key for tailoring therapy to patients' needs. Limited agreement was reached on items regarding breakthrough pain and the management of opioid-induced bowel dysfunction. These findings may assist clinicians in applying clinical evidence to routine care settings and call for a reappraisal of current pain treatment recommendations with the final aim of optimizing the clinical use of strong opioids in patients with cancer.


Prevalence and demographic variation of cardiovascular, renal, metabolic, and mental health conditions in 12 million english primary care records.
Primary care electronic health records (EHR) are widely used to study long-term conditions in epidemiological and health services research. Therefore, it is important to understand how well the recorded prevalence of these conditions in EHRs, compares to other reliable sources overall, and varies by socio-demographic characteristics. We aimed to describe the prevalence and socio-demographic variation of cardiovascular, renal, and metabolic (CRM) and mental health (MH) conditions in a large, nationally representative, English primary care database and compare with prevalence estimates from other population-based studies. This was a cross-sectional study using the Clinical Practice Research Datalink (CPRD) Aurum primary care database. We calculated prevalence of 18 conditions and used logistic regression to assess how this varied by age, sex, ethnicity, and socio-economic status. We searched the literature for population prevalence estimates from other sources for comparison with the prevalences in CPRD Aurum. Depression (16.0%, 95%CI 16.0-16.0%) and hypertension (15.3%, 95%CI 15.2-15.3%) were the most prevalent conditions among 12.4 million patients. Prevalence of most conditions increased with socio-economic deprivation and age. CRM conditions, schizophrenia and substance misuse were higher in men, whilst anxiety, depression, bipolar and eating disorders were more common in women. Cardiovascular risk factors (hypertension and diabetes) were more prevalent in black and Asian patients compared with white, but the trends in prevalence of cardiovascular diseases by ethnicity were more variable. The recorded prevalences of mental health conditions were typically twice as high in white patients compared with other ethnic groups. However, PTSD and schizophrenia were more prevalent in black patients. The prevalence of most conditions was similar or higher in the primary care database than diagnosed disease prevalence reported in national health surveys. However, screening studies typically reported higher prevalence estimates than primary care data, especially for PTSD, bipolar disorder and eating disorders. The prevalence of many clinically diagnosed conditions in primary care records closely matched that of other sources. However, we found important variations by sex and ethnicity, which may reflect true variation in prevalence or systematic differences in clinical presentation and practice. Primary care data may underrepresent the prevalence of undiagnosed conditions, particularly in mental health.


Behavioral influences of proximal alarms.
Confidence in and responses to an unreliable test alarm were studied in the presence of nearby unspecified alarms. The test alarm's reliability rate was represented as averaging "true" only 50% or 60% of the time. Confidence or response rates ranged proportionately from 23% to 97% with the number of active alarms within 5, 6, 7, or 9 annunciator arrays. Adjacent alarms resulted in confidence estimates that were higher (by about 10%) than those with the same number of active alarms spaced up to 3 positions away. Simultaneously activated alarms resulted in a more than 20% increase in "true" responses compared with the same number of alarms offset in time by up to 32 s, regardless of which came first. Active alarms "known" to be functionally related to, or independent of, the test alarm substantially raised or lowered responding but did not completely overcome prior effects. These findings indicate that presumptions that operators' responses are not influenced by nearby alarms, regardless of their function, may be unwarranted. Applications of this research include suggestions to improve responding and training recommendations.


Mitochondrial cytopathies and the kidney.
Mitochondrial cytopathies include a heterogeneous group of diseases that are characterized by impaired oxidative phosphorylation. Current evidence suggests that renal involvement is probably more frequent than originally suspected but remains subclinical in a significant number of patients or is underestimated due to the severity of other clinical manifestations. Until recently, these diseases were thought to develop primarily in pediatric patients but patients that become symptomatic only in adulthood are now well recognized. From a renal standpoint, many patients with severe systemic disease and several patients with oligo-symptomatic clinical pictures have tubular defects, ranging from isolated tubular wasting of electrolytes to complete forms of renal Fanconi syndrome. Aside from rare cases of tubulo-interstitial and cystic diseases, other patients present with glomerular diseases that correspond in the majority of cases to focal segmental glomerulosclerosis lesions. Two specific entities should be singled out, namely the 3243 A>G mutation in the gene encoding for the mitochondrial leucine tRNA because it represents the most frequent form of mitochondrial glomerulopathy, and defects in the biosynthesis of coenzyme Q10 because they represent one of the few treatable forms of mitochondrial cytopathies.


Effects of a Training Program Involving Body Cooling on Physical and Cognitive Capacities and Quality of Life in Multiple Sclerosis Patients: A Pilot Study.
Two methods using exercise and body cooling could influence the well-being of patients with multiple sclerosis (PwMS). The aim of this study was to determine whether wearing a cooling vest during a physical training program could increase the cognitive and physical capacities and quality of life in PwMS. Eighteen PwMS (49.6 ± 8 years; Expanded Disability Status Score 5.0 ± 1.0) were randomly assigned to a cooling or control group. PwMS underwent a 7-week physical training program. In the cooling group, PwMS wore a cooling vest during each training session, whereas in the control group, PwMS wore a cotton T-shirt. Before and after the training program, both groups completed the Isaacs Set Test (IST), Trail Making Test A-B (TMT A-B), SEP-59, Multidimensional Fatigue Inventory and performed a 6-minute walk test (6MWT). The cooling group showed significantly (p < 0.05) improved performance for IST, TMT A and 6MWT. Their emotional well-being and cognitive functions investigated in SEP-59 were significantly (p < 0.05) improved, and general and physical fatigue significantly (p < 0.05) decreased. This physical training program combined with a cooling strategy could have a significant positive influence on both cognitive and physical performances, perceived fatigue and emotional well-being in heat-sensitive PwMS.


Temporal and Spectral Properties of the Auditory Mismatch Negativity and P3a Responses in Schizophrenia.
The mismatch negativity (MMN) event-related potential (ERP) indexes relatively automatic detection of changes in sensory stimuli and is typically attenuated in individuals with schizophrenia. However, contributions of different frequencies of electroencephalographic (EEG) activity to the MMN and the later P3a attentional orienting response in schizophrenia are poorly understood and were the focus of the present study. Participants with a schizophrenia-spectrum disorder (n = 85) and non-psychiatric control participants (n = 74) completed a passive auditory oddball task containing 10% 50 ms "deviant" tones and 90% 100 ms "standard" tones. EEG data were analyzed using spatial principal component analysis (PCA) applied to wavelet-based time-frequency analysis and MMN and P3a ERPs. The schizophrenia group compared to the control group had smaller MMN amplitudes and lower deviant-minus-standard theta but not alpha event-related spectral perturbation (ERSP) after accounting for participant age and sex. Larger MMN and P3a amplitudes but not latencies were correlated with greater theta and alpha time-frequency activity. Multiple linear regression analyses revealed that control participants showed robust relationships between larger MMN amplitudes and greater deviant-minus-standard theta inter-trial coherence (ITC) and between larger P3a amplitudes and greater deviant-minus-standard theta ERSP, whereas these dynamic neural processes were less tightly coupled in participants with a schizophrenia-spectrum disorder. Study results help clarify frequency-based contributions of time-domain (ie, ERP) responses and indicate a potential disturbance in the neural dynamics of detecting change in sensory stimuli in schizophrenia. Overall, findings add to the growing body of evidence that psychotic illness is associated with widespread neural dysfunction in the theta frequency band.


Purification, crystallization and preliminary crystallographic characterization of the caspase-recruitment domain of human Nod1.
The caspase-recruitment domain (CARD) is known to play an important role in apoptosis and inflammation as an essential protein-protein interaction domain. The CARD of the cytosolic pathogen receptor Nod1 was overexpressed in Escherichia coli and purified by affinity chromatography and gel filtration. The purified CARD was crystallized at 277 K using the microseeding method. X-ray diffraction data were collected to 1.9 A resolution. The crystals belong to space group P3(1) or P3(2), with unit-cell parameters a = b = 79.1, c = 80.9 A. Preliminary analysis indicates that there is one dimeric CARD molecule in the asymmetric unit.


Engineering and application of P450 monooxygenases in pharmaceutical and metabolite synthesis.
Cytochrome P450 monoxygenase (P450s or CYPs) allow access to drug metabolites, necessary for approval of new therapeutics in one step, with increased success being demonstrated using bacterial and fungal P450s. Moreover, 12 of the 13 products of the human metabolism of verapamil can be accessed through engineered and chimeric bacterial P450s. These P450s are also used in the synthesis of pharmaceuticals themselves, including the semi-synthetic production of artemisinin in an engineered cell. The integration of new technologies including ultrasound and polyfluorinated hydrocarbon solvents offers an attractive means by the true synthetic potential of ubiquitous P450s can be fully realised.


Construct Validity and Responsiveness of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales and Infant Scales in the PICU.
To assess the construct validity and the responsiveness of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales and Infant Scales in the medical-surgical (PICU) and cardiac PICU. Prospective cohort study of 367 inpatients admitted either to the PICU or the cardiac ICU at Seattle Children's Hospital from January 2012 to June 2013. Parent/caregiver and child (≥ 8 yr old, developmentally appropriate, and critical illness resolved) Pediatric Quality of Life Inventory scores were obtained within 24 hours of PICU/cardiac ICU discharge and subsequently at 4-12 weeks following hospital discharge. Of the 491 eligible participants invited to participate, 367 (74.7% response rate) completed the Pediatric Quality of Life Inventory survey at ICU discharge, and of these, 263 (71.7% follow-up response rate) completed the follow-up survey 4-12 weeks after hospital discharge. Responsiveness was assessed by calculating improvement scores (difference between follow-up and ICU discharge scores, Δ Pediatric Quality of Life Inventory). Construct validity was examined by comparing mean improvement scores for known groups differing by medical complexity. At follow-up, [INCREMENT] Pediatric Quality of Life Inventory scores were as follows (mean ± SD): physical domain, 34.8 ± 32.0; and psychosocial domain, 23.1 ± 23.5. Patients with complex chronic or noncomplex chronic disease had physical functioning improvement scores that were 17.4 points (95% CI, -28.3 to -6.5; p < 0.001) and 19.5 points (95% CI, -30.4 to -8.5; p < 0.002) lower than children with no chronic illness, respectively. Patients with complex chronic disease exhibited psychosocial improvement scores that were 9.6 points (95% CI, -18.4 to -0.8; p < 0.033) lower than patients without chronic disease. Patients with noncomplex chronic disease had similar psychosocial improvement scores when compared with patients without chronic disease. As a measure of health-related quality of live, Pediatric Quality of Life Inventory demonstrated responsiveness and construct validity in a broad population of critically ill children. This measure represents a patient-centered clinically meaningful patient-or-parent-reported outcome measure for pediatric research assessing the clinical effectiveness of PICU/cardiac ICU interventions. When using health-related quality of life recovery as an outcome measure to assess clinical effectiveness in the PICU/cardiac ICU setting, measuring and controlling for the level of medical complexity is important in order to understand the true impact of clinical interventions.


The coexistence of cystic fibrosis and celiac disease.
Two patients with cystic fibrosis (CF) who subsequently developed celiac disease (CD) are described. Since organ culture of intestinal mucosa has been used to establish an in vitro model for the study of CD, we utilized this opportunity to determine whether duodenal mucosa obtained from each of these two patients and their immediate families differed in its organ culture behavior from mucosa obtained from patients with CD alone. Additionally, as specific HL-A types are associated with CD, we used HL-A typing to determine whether the two patients with CF-CD differed genetically from patients with CD alone. One of our patients was HL-A8, the most common type associated with CD; the other was HL-A12, as are many of the non-HL-A8 celiac patients. The response in organ culture of the mucosa of these two patients was the same as the response in organ culture of the mucosa from patients with CD alone. These and other data suggest that CD occurring in patients with CF is no different than CD occurring alone.


Bipolar disorder comorbid with attention-deficit/hyperactivity disorder in adult inpatients with acute relapse.
The aim of this prospective, observational study was to detect the rate of comorbid attention-deficit/hyperactivity disorder (ADHD) in a sample of inpatients diagnosed with bipolar disorder, and to identify differences between patients with bipolar disorder with concomitant ADHD and those without concomitant ADHD. Fifty subjects with bipolar disorder (DSM-IV-TR criteria) aged 18 to 65 years were enrolled in the study in Kingston, Ontario, from October 2008 to April 2010, following their admission to an adult inpatient psychiatric unit during an acute relapse. The Mini-International Neuropsychiatric Interview (MINI) and the ADHD Rating Scale were used to screen the subjects for ADHD and bipolar disorder, while the Hamilton Depression Rating Scale, the Young Mania Rating Scale, and the Global Assessment of Function were used to assess clinical severity at baseline and at 8 weeks. Thirteen (26%) of the enrolled patients rated positive for ADHD on both the MINI and the ADHD Rating Scale. At baseline, no differences were found between the patients with ADHD and those without ADHD with regard to gender, age, length of hospitalization, and severity of clinical and functional deterioration. At 8 weeks, patients with ADHD had lower general scores for depression (P = .025) than those without ADHD. In a psychiatric inpatient sample, patients with bipolar disorder and ADHD were not more severely ill in the acute phase and did not have a poorer outcome at 8 weeks.


Posttraumatic thumb reconstruction.
After reading this article, the reader should be able to: 1. Discuss the critical anatomic features of the thumb as they affect on reconstructive decision making. 2. Define the goals of reconstruction. 3. Discuss an algorithm for thumb reconstruction according to the level of amputation. 4. Understand the role of prosthetics in thumb reconstruction. The function of the thumb is critical to overall hand function. Uniquely endowed with anatomic features that allow circumduction and opposition, the thumb enables activities of pinch, grasp, and fine manipulation that are essential in daily life. Destruction of the thumb secondary to trauma represents a much more significant loss than would result from loss of any other digit. Therefore, significant effort has been focused on thumb reconstruction. Numerous techniques have been described, ranging from simple osteoplastic techniques to complex microsurgical procedures. With an appreciation of the unique anatomic properties of the thumb, the hand surgeon is better able to understand the goals of thumb reconstruction and to develop an algorithm for thumb reconstruction. With such an understanding, an individualized reconstructive plan can be developed for each patient. A great many options are available for posttraumatic thumb reconstruction. Optimal results are obtained by pursuing an organized and logical approach to reconstruction based upon the level of tissue loss. Reconstruction methods depend on the location of the amputation and range from homodigital and heterodigital flaps to partial-toe transfer or a great-toe wrap-around flap to first-web-space deepening using Z-plasties, a dorsal rotation flap, or a distant flap, to distraction osteogenesis, lengthening of the thumb ray, spare parts from another injured digit in the acute setting for pollicization or heterotopic replantation, and microvascular toe transfer. Amputations in the distal third of the thumb are generally well-tolerated. The primary reconstructive issues are the restoration of a padded and sensate soft-tissue cover, as well as aesthetic considerations. First-web-space deepening will generally provide excellent results for amputations at the distal half of the middle third. In the proximal half of the middle third, lengthening of the thumb ray is generally required. Distraction lengthening of the first metacarpal is a useful and reliable technique that provides up to 3 cm of length without requiring complex microsurgical methods. Spare parts from another injured digit may be used in the acute setting for pollicization or heterotopic replantation. Microvascular toe transfer is an excellent option for elective reconstruction. However, other options also are available and may be more appropriate in some cases. Less ideal options include the various types of osteoplastic reconstruction. The reconstruction of posttraumatic thumb defects is a challenging and rewarding surgical endeavor. The value of a functioning thumb is immense, and its reconstruction is worthy of considerable effort. Despite the elegant reconstructive options available, the best results are obtained with replantation or revascularization whenever possible. Finally, the treatment plan always must be derived from a careful assessment of each patient's posttraumatic function and specific reconstructive needs.


The 'auxiliary' white coat effect in hospitals: perceptions of patients and doctors.
A doctor's attire is important in making a positive first impression and enhancing the overall healthcare experience for patients. We conducted a study to examine the perceptions and preferences of patients and doctors regarding six types of dress codes used by doctors in different scenarios and locations. A total of 87 patients and 46 doctors participated in the study. Separate sets of questionnaires containing four demographic questions and 14 survey questions were distributed to the two groups. Most patients preferred doctors to dress formally in white coats regardless of the scenario or location, whereas the majority of doctors preferred formal attire without white coats. Both groups preferred operating theatre attire in the emergency department. Our findings confirmed that patients perceived doctors in white coats to be more trustworthy, responsible, authoritative, confident, knowledgeable and caring. There is a need to educate the public about the reasons for changes in doctors' traditional dress codes.


Data collection automation and total quality management: case studies in the health-service industry.
The limitations, immeasurable, and seemly unquantifiable aspects of the healthcare service industry, make it imperative that quality assurance programs include total quality management (TQM) and automatic identification and data capture (AIDC)-related technologies. Most of standards used in TQM and AIDC require data, to measure improvement and achieve standardization. Major difference between managing a service firm and managing a product-manufacturing firm is the difficulty of achieving consistently high quality. Examination of two different healthcare service providers in the Pittsburgh, Pennsylvania area offers different views as to the implementation and practice of total quality management techniques and AIDC integration. Since the healthcare service industry must take into account its high customization needs, there are positive steps to make the hospital structure itself more patient friendly and quality related; hence improving its heath-marketing strategies to the general public.


Fluorine-Free Superhydrophobic Covalent-Organic-Polymer Nanosheet Coating for Selective Dye and Emulsion Separation.
Covalent organic polymer nanosheets (COPNs) endowed with porous networks and large surface areas in their structures offer great advantages over other materials in addressing environmental problems. In this study, fluorine-free superhydrophobic COPNs were designed and applied to selective dye absorption. Notably, COPNs selectively adsorb dyes with a high hydrophobic index (HI) and reject low HI dyes with maximum adsorption capacities of 361 and 263 mg/g for crystal violet and methylene blue, respectively. The adsorption isotherm model showed that the COPNs follow the Langmuir adsorption isotherm model and pseudo-second-order kinetics. Next, we explored the superhydrophobicity of the COPNs by in situ fabrication with melamine sponge (COPNs-MS), which incorporates the superhydrophobicity of COPNs [water contact angle (WCA) of >150°] with the structure and flexibility of the MS skeleton. The COPNs-MS shows various oil-adsorbing properties with good adsorption capacity (from 60 to 120 g/g) and also effectively separates various surfactant-stabilized emulsions with a separation efficiency of over 99%. The as-fabricated COPNs-MS retains its superhydrophobicity in various solvents and hazardous conditions (WCA ≥ 150°) and exhibits good flame retardancy and excellent compression properties with excellent antifouling property due to the superhydrophobic COPN coating. Furthermore, COPNs-MS also demonstrates excellent recyclability because the strong COPN coating in the MS skeleton retains its hydrophobicity. Therefore, our fluorine-free superhydrophobic COPNs are not only capable of selective dye adsorption but also exhibit very good oil adsorption and surfactant-stabilized emulsion separation performance.


Metformin Prescription Associated with Reduced Abdominal Aortic Aneurysm Growth Rate and Reduced Chemokine Expression in a Swedish Cohort.
Recent reports suggest that the negative association between diabetes mellitus and abdominal aortic aneurysm (AAA) may be driven by metformin, the world's most common antidiabetic drug rather than diabetes per se. We sought to investigate the association among AAA growth rate, chemokine profile, and metformin prescription in a contemporary Swedish cohort. Patients under surveillance for small AAA were identified at 4 Swedish vascular centers with active AAA screening programs. Annual AAA growth rate, medical history, and prescribed medications were recorded for linear regression analysis. In a subset of patients with AAA and control subjects without AAA or diabetes, plasma samples were available and analyzed for 40 inflammatory chemokines. A total of 526 patients were included for AAA growth analysis: 428 without type 2 diabetes mellitus (T2DM), 65 with T2DM and metformin prescription, and 33 with T2DM but without metformin prescription. Patients were included from 2005 to 2017 with mean follow-up of 3.2 (1.7) years and median annual AAA growth rate 1.6 mm, range -4.8 to 15.4 mm. Mean (standard deviation) annual AAA growth rates were 2.3 (2.2) mm in non-T2DM patients versus 1.1 (1.1) mm in patients with T2DM with metformin prescription and 1.6 (1.4) mm among those with T2DM without metformin prescription. With non-T2DM patients as reference in an unadjusted and 2 adjusted models, metformin prescription was significantly associated with reduced AAA growth rate (P < 0.001, P = 0.005, and P = 0.024, respectively), but not T2DM without metformin prescription (P = 0.137, P = 0.331, and P = 0.479, respectively). Among 240 patients with AAA (152 without T2DM, 51 with T2DM and metformin, and 37 with T2DM without metformin) and 59 without AAA or T2DM, metformin prescription was associated with reduced expression of chemokines representing all classes of leukocytes. Metformin prescription is associated with reduced AAA growth rate, possibly mediated by broad anti-inflammatory effects. A randomized controlled trial is needed to determine what role metformin may play in AAA disease, particularly in the absence of T2DM.


Wnt Pathway in Bone Repair and Regeneration - What Do We Know So Far.
Wnt signaling plays a central regulatory role across a remarkably diverse range of functions during embryonic development, including those involved in the formation of bone and cartilage. Wnt signaling continues to play a critical role in adult osteogenic differentiation of mesenchymal stem cells. Disruptions in this highly-conserved and complex system leads to various pathological conditions, including impaired bone healing, autoimmune diseases and malignant degeneration. For reconstructive surgeons, critically sized skeletal defects represent a major challenge. These are frequently associated with significant morbidity in both the recipient and donor sites. The Wnt pathway is an attractive therapeutic target with the potential to directly modulate stem cells responsible for skeletal tissue regeneration and promote bone growth, suggesting that Wnt factors could be used to promote bone healing after trauma. This review summarizes our current understanding of the essential role of the Wnt pathway in bone regeneration and repair.


Frequency of the severe combined immunodeficiency disease gene among horses in Morocco.
Severe combined immunodeficiency disease (SCID) of horses is an autosomal, recessive hereditary disease occurring among Arabian or crossbred Arabian horses. The genetic defect responsible was previously identified as a 5-base pair deletion in the gene encoding the catalytic subunit of the DNA dependant protein kinase (DNA-PKcs). This study was carried out to determine the frequency of SCID and identify horses carrying the gene for SCID among Arabian and Arabian crossbred stallions and mares in Morocco using a DNA-based test. Twenty-one horses were SCID carriers: 14 (7%) Arabians, 6 (4%) Arab-Barbs and one (33%) Anglo-Arab. After analysing their genealogy, 3 imported stallions were identified that disseminated the mutant gene of DNA-PKcs in Morocco.


The equine hypophysis: a gland for all seasons.
The intrahypophysial mechanisms involved in the control of gonadotrophin secretion remain unclear. In the horse, a divergent pattern of gonadotrophins is observed at different stages of the reproductive cycle in response to a single secretagogue (gonadotrophin-releasing hormone), and dramatic changes in fertility take place throughout the year in response to photoperiod. This species thus provides a useful model to investigate the regulation of fertility directly at the level of the hypophysis. A series of studies were undertaken to examine the cytological arrangements and heterogeneity of gonadotrophin storage in the pars distalis (PD) and pars tuberalis (PT) of the hypophysis of male and female horses. Specifically, the seasonal and gonadal effects on distribution, density and hormonal identity of gonadotrophs, the existence of gonadotroph-lactotroph associations and the expression of prolactin receptors (PRL-R) as possible morphological bases for the differential control of gonadotrophin secretion were investigated. It became apparent that both isolated and clustered gonadotrophs are normally distributed around the pars intermedia and surrounding capillaries in the PD, and in the caudal ventral region of the PT. In the PD, no effects of season or of reproductive state on the density or number of gonadotrophs could be detected in either male or female animals. In contrast, a fivefold increase in gonadotroph density was observed in the PT during the sexually active stage. In males, robust gonadal effects were detected on the gonadotroph population; orchidectomy significantly reduced both the number and proportion of gonadotrophs, in relation to other hypophysial cell types, in both the PD and PT regions. Luteinizing hormone (LH) monohormonal, follicle-stimulating hormone (FSH) monohormonal and bihormonal gonadotrophs were identified in the PD and PT of male and female horses. Interestingly, in males, the relative proportions of gonadotroph subtypes and the LH/FSH monohormonal gonadotroph ratio were not affected by either season or the presence of the gonads. In contrast, a larger proportion of monohormonal gonadotrophs was clearly observed in sexually active females. Specific gonadotroph-lactotroph associations and expression of PRL-R in cells other than gonadotrophs were detected in the PD throughout the annual reproductive cycle. In addition to a stimulatory gonadal effect on lactotroph density, a substantial gonadal-independent effect of season was apparent on this variable. The findings have revealed important seasonal and gonadal effects on the cytological configuration of the equine hypophysis, which may provide the morphological basis for the intrahypophysial control of fertility.


The Man Who Saw Things on Carvedilol.
The newer generation non selective vasodilating beta adrenergic blocking agent Carvedilol, also has an alpha 1 adrenoceptor antagonistic effect and is widely used in treating various cardiovascular diseases. It is a selective alpha and non-selective beta blocker. It's side effects are vast and not limited to any particular organ system, the neuropsychiatric adverse effects include; somnolence, nervousness, sleep disorder, aggravated depression, vivid dreams, delirium, psychosis, impaired concentration, abnormal thinking, paroniria, and emotional lability. Hallucinations are rarely reported and as far as we know the only reported couple of cases were on metoprolol and propranolol, none has been reported with Carvedilol.


Prevalence of TMJ symptoms and X-ray findings.
Some results of the fifteen year longitudinal Groningen study on TMJ dysfunction are reported. The prevalence of subjectively communicated symptoms appears to consistently increase with age. The recording of 21 percent pain at the last check-up was judged high. Objectively determined symptom frequencies (in the literature sometimes indicated signs) seem to level off in the early twenties. Observed X-ray deformities or flattening of the condyle did not increase substantially. The symptoms registered at the successive time points were found to originate to a considerable extent from changing individuals, indicating the unstable character of these symptoms. Furthermore the symptom categories are rarely present simultaneously in one individual. In harmony with these findings it appeared to be nearly impossible to predict any component by the same or any other component at an earlier time point. It is concluded that during growth, and probably due to growth, different signals appear. Some are outgrown, others are followed by serious problems; a third group may develop a new problem at maturity. Future research will be directed to identify these different groups at an early stage.


Sweet and sour: an update on classic galactosemia.
Classic galactosemia is a rare inherited disorder of galactose metabolism caused by deficient activity of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme of the Leloir pathway. It presents in the newborn period as a life-threatening disease, whose clinical picture can be resolved by a galactose-restricted diet. The dietary treatment proves, however, insufficient in preventing severe long-term complications, such as cognitive, social and reproductive impairments. Classic galactosemia represents a heavy burden on patients' and their families' lives. After its first description in 1908 and despite intense research in the past century, the exact pathogenic mechanisms underlying galactosemia are still not fully understood. Recently, new important insights on molecular and cellular aspects of galactosemia have been gained, and should open new avenues for the development of novel therapeutic strategies. Moreover, an international galactosemia network has been established, which shall act as a platform for expertise and research in galactosemia. Herein are reviewed some of the latest developments in clinical practice and research findings on classic galactosemia, an enigmatic disorder with many unanswered questions warranting dedicated research.


Biotransformation and biological activity of N-(4-hydroxyphenyl)retinamide derivatives in rodents.
The metabolism and bioactivity of N-(4-hydroxyphenyl)-all-trans-retinamide (HPR) and of various O-alkyl and ester derivatives of HPR were investigated in rodents. The principal metabolite of HPR in tissues is N-(4-methoxyphenyl)-all-trans-retinamide. N-(4-methoxyphenyl)all-trans-retinamide is equipotent to HPR in reversing keratinization of retinoid-deficient hamster trachea in vitro. Another nonpolar metabolite of HPR is also present in tissue and (although not positively identified) is thought to be a long-chain fatty acid ester of HPR. HPR is excreted into rat bile as numerous polar retinamides, including HPR-O-glucuronide. The rate of hydrolysis of HPR esters by rat serum and hepatic enzymes in vitro is inversely related to the length of the esterified acid side group. After a 30-min incubation at 37 degrees C in serum, percentage of hydrolysis for acetyloxy, propionyloxy, butyryloxy, pivaloyloxy and octanoyloxy esters of HPR is 41, 20, 7.5, 1.9 and 1.5, respectively. In contrast, hydrolysis by hepatic esterases is more rapid, particularly for the pivaloyloxy ester. Potency of the various HPR esters in the tracheal organ culture bioassay decreases as the length of the esterified side group increases; the acetyloxy ester is at least 5 times more potent than the octanoyloxy ester.


A Preliminary Study of Correlates of Premature Birth and Their Influence on Cortisol Levels in Young Children.
The HPA-axis is programmed during early infancy, but a lot is unknown about the programming of the HPA-axis in prematurely born or small for gestational age (SGA) children. Therefore, the aim of this preliminary study was to investigate the influence of prematurity and variables associated with birth on cortisol levels in young children. Cortisol was measured in a cross-sectional design in 38 premature born participants (<37 weeks of gestation), aged between 3 - 9 years old. Correlates of prematurity (degree of prematurity and birth delivery route) were investigated in relationship with cortisol levels with regression analysis. Corrected for sex, delivery by C-section was associated with lower cortisol levels in the children (ß = -.42, p = .028), with an explained variance of 34%. Birth delivery route by C-section is associated with lowered (or flattened) cortisol levels in children born prematurely. This is clinically relevant and might have important implications, because an HPA-axis disturbance might lead to developmental problems later on in life. However, future research is necessary to investigate the underlying indications for performing a C-section, which will help to understand factors that influence the HPA-axis development in children born prematurely.


Immature patients in a mature system: Regional analysis of Florida's pediatric trauma system.
The state of Florida's trauma system is organized into seven regions, two of which lack designated pediatric trauma centers. Injured children residing in these regions often require transfer out of their home region for definitive care. The purpose of this study was to evaluate the effectiveness and efficiency of the current regionalization approach, focusing on variations between regions. Using the Florida Agency for Health Care Administration database, we identified all trauma patients 15 years old or younger admitted between 2009 and 2014. Patients with high-risk injury (ICD-9 Injury Severity Score < 0.85) who did not receive definitive treatment at a pediatric trauma center (PTC) were considered undertriaged. Outcomes of interest included mortality and long-term disability. Patients who were definitively treated at a facility outside their home region, but who had low risk injuries (ICD-9 Injury Severity Score > 0.9), required no procedures or ICU monitoring, and were discharged within 48 hours, were considered to have received potentially avoidable out-of-region treatment. Regions were compared, and patients treated in-region were compared to those treated out-of-region. Regression models were used to adjust for covariates. Of 34,816 patients, 8% had high-risk injuries and the overall mortality rate was 1%. Risk-adjusted outcomes were generally similar across all regions. Regional rates of undertriage varied from 0.4% to 4.7% and were highest in regions lacking a PTC. Eleven percent of patients required definitive treatment outside their home region; these patients had higher hospital charges and stayed in the hospital 0.96 days longer (least-squares mean). Rates of potentially avoidable out-of-region treatment ranged from 7% to 12% in the two regions lacking a PTC. After adjustment for confounders, significant unexplained differences in potentially avoidable out-of-region treatment remained between these two regions (OR 2.0, 95% CI 1.6-2.6). Florida's regionalized pediatric trauma system performs effectively, with low undertriage and acceptable outcomes. Out-of-region treatment, an inevitable byproduct of the current regionalization approach, imposes a measurable burden on the treating facility and patient/family. Unexplained variations in potentially avoidable out-of-region treatment suggest improvements can be made in system efficiency. Economic/decision study, level III.