Pocket-size solid-state iPOD and flash drives for gigabyte storage, display and transfer of digital medical images: Review and work initiated.
A locally assembled image viewer system with pocket-size iPOD (80 GB) and flash (2 GB) drives for gigabyte storage, display and transfer of digital medical images, oriented towards training purposes, is described. Both the iPOD and flash drive enable storage of thousands of images from diverse medical-imaging equipments. The iPOD, in addition, can display with sufficient resolution any of these images and serves as a transportable preview device. Through the use of a computer, these devices can access/ store/ display the images/ photos from a CD, digital camera or the internet. A TV image viewing unit is also provided. The operational features and the advantages of these devices are discussed in detail. The quality assurance (QA) of the displays has been successfully carried out with standard test patterns. The image quality has been tested with dynamic and static medical images. The system will be highly useful for storage and remote display of multitude of images from several modalities in the hospital, as well as other images, from the point of view of education and training. It has good potential for use in clinical diagnosis as well. Other recent advancements using iPHONE and improved but expensive computers, integrated with picture archiving and communication system (PACS) as well as radiology and hospital information system (RHIS) for versatile applications in modern radiology, are also highlighted.This system, assembled with indigenous equipments, is much less expensive and specially suited for teaching radiologists, physicists and technologists, particularly in developing countries.


Increasing sensing resolution with error correction.
The signal to noise ratio of quantum sensing protocols scales with the square root of the coherence time. Thus, increasing this time is a key goal in the field. By utilizing quantum error correction, we present a novel way of prolonging such coherence times beyond the fundamental limits of current techniques. We develop an implementable sensing protocol that incorporates error correction, and discuss the characteristics of these protocols in different noise and measurement scenarios. We examine the use of entangled versue untangled states, and error correction's reach of the Heisenberg limit. The effects of error correction on coherence times are calculated and we show that measurement precision can be enhanced for both one-directional and general noise.


Self-esteem mediates the relationship between spirituality and subjective well-being in Iran.
Self-esteem appears to play a central role in the spiritual life and ethical behaviour of the typical Iranian. For example, for many Iranians, humankind is believed to be the crown of creation, and each person is believed to be individually valued by God. Previous empirical studies also indicate that in Iran spirituality is positively associated with self-esteem. On this basis, it was hypothesised that self-esteem would be one of the mechanisms through which spirituality leads to increased mental well-being. Mediation analysis showed that self-esteem was a partial mediator of the spirituality-well-being relationship. Moreover, results of moderated mediation analysis revealed that this mediation was not significantly moderated by gender, and that the indirect path through self-esteem was significant in both genders. Implications of the results and their relevance to other western and eastern religions (e.g. Christianity and Buddhism) are discussed.


[The influence of retinol, tocopherol and cimetidine on the ulcerogenic effect of Orthofen, indomethacin and naproxen].
The influence of retinol, alpha-tocopherol, and cimetidine on ulceration induced by ortophen, indomethacin, naproxen was studied on rats. It was shown that alfa-tocopherol, retinol, and cimetidine reduce the damaging effect of these drugs on the gastroduodenal mucosa of rats thus normalizing the phospholipid content. The influence of alpha-tocopherol and retinol on the side-effects of ortophen was studied in children with rheumatoid arthritis. Ortophen was found to cause gastroduodenal side-effects in more than 30% of patients and decrease the levels of vitamin A and E in children. The use of retinol and alpha-tocopherol in cotherapy decreases the frequency and severity of side-effects and reduces the vitamin deficiency.


Effect of stress-related hormones on inner ear fluid homeostasis and function.
Induction of suprathreshold levels of stress-related hormone by systemic administration of epinephrine can change inner ear fluid homeostasis and function. Meniere's disease is frequently associated with high levels of anxiety and other forms of psychological disturbance. Most clinicians agree that emotional stress or severe anxiety can precipitate relapse or aggravate the symptoms. In general, it is known that stress-related hormones such as epinephrine, norepinephrine, vasopressin, aldosterone, and cortisol are released into systemic circulation in response to stress. Significantly higher levels of plasma norepinephrine and vasopressin in patients with Meniere's disease have been reported. Concentrations of sodium and potassium in perilymph were measured by a flame photometer after systemic infusion of epinephrine (6.3 microg/min for 3 hours). Control animals were treated with equal volumes of 0.9% physiologic saline. Compound action potentials (CAP) elicited by brief tone bursts were measured before and 3 hours after the infusion of epinephrine. For chronic studies, epinephrine (10 microg/d/kg) was given by osmotic pump implanted subcutaneously for 1, 2, 3, and 4 weeks, respectively. Click- and tone-evoked auditory brain responses (ABRs) were measured at 1, 2, 3, and 4 weeks after epinephrine administration. Concentrations of sodium and potassium increased significantly in perilymph (p < 0.001 and p < 0.01) after epinephrine infusion over controls. The osmolality increased significantly in serum and perilymph after epinephrine infusion. The CAP threshold was significantly elevated at all frequencies. The shift of the CAP threshold caused by epinephrine tended to be larger at higher frequencies. In chronic studies, epinephrine administration caused a transient 20 to 45 dB threshold shift that increased with time and was relatively constant across frequency. There is good evidence to suggest that stress-related hormones such as epinephrine can alter inner ear fluid homeostasis and auditory function. This study confirmed this hypothesis and illuminated the processes of alteration by demonstrating specific changes in perilymph composition and auditory function.


[Incidence of gastric cancer in the 02 health area of Castellon].
We retrospectively reviewed 169 cases of gastric carcinoma diagnosed between 1992 and 1994 in a population of 349,318 inhabitants included in Health Zone 02 in the province of Castellon. These 169 cases correspond to an incidence ratio of 16.1 cases/100,000 inhabitants/year. Males were affected more frequently than females in a 2/1 ratio. Additionally, a male predominance exists at younger ages, however below the age of 30 the incidence in males and females was similar. Pathologic findings showed that the diffuse type gastric adenocarcinoma was more frequently encountered (57.4%) than the Lauren's intestinal type. Overall, the risk of gastric adenocarcinoma in the zones that was studied was higher than in the other two provinces of the Comunidad Valenciana.


Origin of reproductive isolation in the absence of apparent genic differentiation in a geographic isolate of Drosophila pseudoobscura.
F(1) males obtained from the cross of D. pseudoobscura females from Bogotá (Colombia) x males of this species from mainland, i.e. populations from various locations in the United States and from Guatemala, are sterile. This sterility is due to genes located on the X chromosome and the autosomes; the Y chromosome is not involved. The percentage of sterile males in backcrosses can be explained by assuming an interaction between two loci on the Bogotá X chromosome and probably two loci, one each on two of the mainland autosomes. The role of founder events, inbreeding and geographic isolation in the development of reproductive isolation and the magnitude of gene differences responsible for the origin of reproductive isolation is discussed. It is concluded that founder events, inbreeding and geographic isolation play a major role in the development of reproductive isolation and that major adaptive incorporation of new alleles at a large number of structural loci is not necessary for the origin of reproductive isolation.


Tumor microenvironment of adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATLL) is a malignancy caused by the human T-cell leukemia virus type 1. Aggressive ATLL is refractory to conventional chemotherapy and has a poor prognosis. Better therapeutic approaches, including cancer immunotherapy, are required to improve survival and prognosis. The genetic landscape of ATLL reveals frequent genetic alterations in genes associated with immune surveillance, including major histocompatibility complex (MHC) class I, CD58 antigen, and programmed cell death ligand 1. Clinicopathological investigations also revealed tumor immunity mechanisms in ATLL, including immune checkpoint molecules, MHC molecules, tumor-associated macrophages, and chemokines. However, the tumor microenvironment of ATLL remains complex because ATLL itself originates from T-cells, usually expressing regulatory T-cell markers. In this review, we discuss the recent literature describing the tumor microenvironment of ATLL.


Transition metal complexes with oligopeptides: single crystals and crystal structures.
The coordination chemistry of short chain peptides with transition metals is described in terms of the available crystal structures. Despite their high interest as synthetic models for metalloproteins and as building blocks for molecular materials based on the tuneable properties of oligopeptides, single crystal X-ray diffraction studies are scarce. A perusal of the most relevant results in this field allows us to define the main characteristics of oligopeptide-metal interactions, the fundamental problems for the crystallization of these complexes, and some hints to identify future promising approaches to advance the development of metallopeptide chemistry.


Role of calcitonin gene-related peptide in gastric hyperemic response to intragastric capsaicin.
Stimulation of sensory neurons in the rat stomach by intragastric capsaicin leads to a marked rise in gastric mucosal blood flow (GMBF). The gastric mucosa, in particular submucosal blood vessels, is densely innervated by afferent neurons containing peptides, of which calcitonin gene-related peptide (CGRP) is the most potent vasodilator. Using selective ablation of either the vagal or spinal sensory innervation to the stomach by perineural application of capsaicin, and by intra-arterial infusion of the CGRP receptor antagonist hCGRP-(8-37) close to the stomach, we investigated 1) the origin (vagal or spinal) of the sensory neurons and 2) whether CGRP mediates this hyperemic response. Perivagal application of capsaicin to the rat 10-20 days before experiments had no effect on the hyperemic response to intragastric capsaicin. In contrast, periceliac application of capsaicin significantly reduced this response by 60%. Intra-arterial infusion of CGRP (20 pmol/min) close to the stomach produced a marked rise in GMBF and this was completely blocked by hCGRP-(8-37) (500 pmol/min). intra-arterial infusion of hCGRP-(8-37) or its vehicle, bovine serum albumin, had no significant effect on basal GMBF. However, the increment in GMBF in response to intragastric capsaicin was significantly attenuated by 79%. We conclude that 1) spinal sensory neurons innervating the gastric mucosa partially mediate the increase in GMBF induced by intragastric capsaicin and 2) CGRP is the major vasodilator released by these fibers.


Cationic liposomes for gene delivery: from biophysics to biological applications.
The use of an efficient carrier for nucleic acid-based medicines is considered to be a determinant factor for the successful application of gene therapy. The drawbacks associated with the use of viral vectors, namely those related with safety problems, have prompted investigators to develop alternative methods for gene delivery, cationic lipid-based systems being the most representative. Despite extensive research in the last decade on the use of cationic liposomes as gene transfer vectors and the development of elegant strategies to enhance their biological activity, these systems are still far from being viable alternatives to the use of viral vectors in gene therapy. In this review considerations are made regarding the structure-activity relationships of cationic liposome/DNA complexes and the key formulation parameters influencing the features of lipoplexes are presented and discussed in terms of their effect on biological activity. Particular emphasis is given to the interaction of the lipoplexes with serum components as well as to novel strategies developed to circumvent difficulties that may emerge upon iv administration of the complexes. Finally, since the ability of the lipoplexes to be stored while preserving their transfection activity is a crucial issue for the repeated use of such carriers, approaches reported on the improvement of their physical stability are also reviewed.


Improved free musculocutaneous flap survival with induction of heat shock protein.
The cellular response to a wide variety of stresses results in the synthesis of a family of stress response proteins termed heat shock proteins. Recent studies have demonstrated that heat shock proteins produced in response to an initial stress seem to protect against subsequent unrelated stresses. Importantly, hyperthermia-induced heat shock proteins provided protection from ischemia/reperfusion injury in several organ transplantation models. We hypothesized that free musculocutaneous flap survival could be improved by enhancing the flap's tolerance to relative ischemia by the prior induction of heat shock proteins. Accordingly, we determined the heat shock protein response in skin and muscle after systemic or local heating and examined the effect on free musculocutaneous flap survival in a rat model. Free musculocutaneous flaps incorporating thigh adductor muscles and a 2 x 6-cm2 skin paddle were transplanted to the ipsilateral groin in three groups of male Wistar rats. Systemically heated rats (n = 6) were anesthetized and incubated for 30 minutes at 42 degrees C 6 hours before free musculocutaneous tissue transfer. Locally heated rats (n = 6) were anesthetized, and their donor site anterior thigh was placed for 30 minutes on a heating block set at 44 degrees C 6 hours before free tissue transfer. Control rats (n = 5) did not have heating pretreatment but underwent identical anesthesia. Animals were sacrificed on postoperative day 3, at which time skin loss (cm2) and muscle viability, quantified by nitroblue tetrazolium staining time, were assessed in a blinded fashion. The skin and muscle from the free flap were analyzed for HSP72 mRNA and protein using quantitative Northern and Western blot techniques. All free musculocutaneous flaps were viable. However, the locally and systemically heated rats demonstrated a marked improvement of skin survival, which correlated with increased skin levels of HSP72. There were no differences in nitroblue tetrazolium muscle staining times or muscle levels of HSP72 among the three groups. These findings suggest that prior heat-induced heat shock proteins result in improvement in musculocutaneous flap survival, which may have direct clinical applications, especially in high-risk patients.


Immobilized N-methyl-D-glucamine as an arsenate-selective resin.
Immobilization of N-methyl-D-glucamine (NMDG) on poly(vinylbenzyl chloride) beads yields an effective and highly selective sorbent for arsenate ions. Three important parameters in the resin's high As(V) affinity and selectivity are the structure of the ligand, its ionic form, and the crosslink density of the polymer. The NMDG resin crosslinked with 2 wt % divinylbenzene is far more selective than commercially available analogues, especially when sulfate and chloride ions are present in solution at high concentrations. Selectivity studies at neutral pH indicate that the protonated tertiary amine moiety is an important component of the complexation mechanism. The NMDG resin also has a high affinity for the un-ionized As(V) species at pH 1.


MADS-box genes expressed during tomato seed and fruit development.
MADS-box genes in plants are putative transcription factors involved in regulating numerous developmental processes, such as meristem and organ identity in inflorescences and in flowers. Recent reports indicate that they are involved in other processes than flower development such as the establishment of developing embryos, seed coat and ultimately in root and fruit development. We have identified seven tomato MADS-box genes that are highly expressed during the first steps of tomato fruit development. According to comparisons of their deduced amino acid sequences, they were classified into two groups: (1) already identified tomato MADS-box genes previously defined as flower identity genes (TAG1, TDR4 and TDR6) and (2) new tomato MADS-box genes (TAGL1, TAGL2, TAGL11 and TAGL12). With the exception of TAGL12, which is expressed near uniformly in every tissue, the other genes show an induction during the tomato fruit development phase I (anthesis) and phase II, when active cell division occurs. In situ hybridization analyses show a specific expression pattern for each gene within the fruit and embryo sac tissues suggesting an important role in the establishment of tissue identity. Yeast two-hybrid analyses indicate that some of these proteins could potentially form dimers suggesting they could act together to accomplish their proposed role.


Double heterozygous mutations Gln100Leu and His348Gln of the F7 gene in a patient with factor VII deficiency.
A 25-year-old Chinese woman who had a history of easy bruising was admitted to hospital due to uncontrolled epistaxis. She showed factor VII activity level of 2% and factor VII antigen level of 4% of the normal value. We detected a novel missense mutation g.8355 A>T (p.Gln100Leu) in the second epidermal growth factor-like (EGF) domain and a g.11482 T>G (p.His348Gln) in the catalytic domain. Although the Gln100 residue is close to the junction of EGF-2 domain with the serine protease domain, we infer that the substitution of polar negatively charged Gln residue at the position 100 with introduction of nonpolar Leu residue may be likely to perturb proper folding, resulting in decreasing factor VII activity.


[The synergistic action of quaternary ammonium derivatives and inhibitors of nitrate reduction in respect to Pseudomonas aeruginosa].
It was revealed that ability of zink chloride, copper sulphate, aluminium nitrate and sodium chloride to inhibit the nitrate reduction of Pseudomonas correlated with their potentiating influence on the antimicrobial activity of decamethoxin, a quaternary ammonium derivative. So, doses of zink chloride (0.01-0.04%), copper sulphate (0.04%), aluminium nitrate (0.04%), sodium fluoride (0.05-0.1%) able to inhibit effectively the reduction of anions of nitric acid decreased the minimal inhibitory concentration of decamethoxin against Pseudomonas strain ATCC 27853 to 0.15-10 mg/ml and minimal bactericidal concentration to 0.20-10 mg/ml in comparison with 15.6 and 60.4 mg/ml in the control without potentiators. Providing the use of respiration chain's inhibiting doses of sodium fluoride (0.1%) and zink chloride (0.01%), it became possible to decrease the resistance of 54 clinical samples of Pseudomonas aeruginosa to decamethoxin.


Thai-shock survey 2013: survey of shock management in Thailand.
Pragmatic surveys for shock management by Thai physicians are unavailable. The objective of this study is to identify the shock management patterns on both; the incidence of septic shock and hemorrhagic shock here in Thailand. Two thousand questionnaires were sent to physicians who are called on to care for patients in shock across Thailand. The questionnaire is composed of 58 items regarding all aspects of the management of septic and hemorrhagic shock. A frequency scale has been defined by 5 levels of patient proportion estimates from routine practices. Between April and August, 2013, 533 of the distributed questionnaires (26.7%) were returned. In severe sepsis and septic shock management, 406 physicians (76.2%) have reported the routine use of the quantitative resuscitation protocols. Urine output, mean arterial pressures and central venous pressures have been more frequently used than central venous oxygen saturation and lactate levels for the resuscitation goals. Nearly 80% of these clinicians have shown "often and always" for the achievement of the resuscitation goals within 6 hours. Most of the physicians (65.3%) had never used procalcitonin biomarkers. Antimicrobial empirical treatments were started within 1 hour of admission for 87.7% of these patients and were continued for less than 5 days in 67.3% of the cases prior to de-escalating the treatments. Crystalloids have been the common, initial fluid used for resuscitation (98.9% in sepsis, 99.3% in trauma). The most commonly used vasopressors are norepinephrine (69.6%) for sepsis and dopamine (63.1%) for trauma. The median of the cortisol threshold level for steroid replacement therapy is 15 mg/dL, taken from the interquartile range or IQR of 5-19 mg/dL. Nearly all the physicians currently use hydrocortisone (96.4%). The median daily dose of hydrocortisone is 300 mg (IQR; 200-300). Approximately 50% of the physicians prescribed the hydrocortisone in divided doses to be administered every 8 hours and 31.8% ordered the medications as a continuous infusion. Tapering the dose in reduction varied by 33.6% ofthe physicians over a period of 2 to 3 days. Central venouspressures (CVP) and fluid challenge tests were more frequently used in the evaluation ofpreload rather than some of the newer fluid responsiveness methods. Less than 15% of the physicians continued to use pulmonary artery catheters in their routine practices. Regarding hemorrhagic and traumatic shock, only 162 physicians (39.3%) have been certified in Advance Traumatic Life Support (ATLS), but 311 physicians (75.6%) have reported in following with the ATLSguidelines. In patients requiring massive transfusions, physicians used packed red cells (PRC) and fresh frozen plasma (FFP) in a ratio of 1:1 (34.1%). Focus assessment sonography for trauma (FAST) was the most commonly used diagnostic method in cases of traumatic shock. Most physicians manage shock with the current protocols. Hemodynamic goals are preferred over tissue perfusion targets. Early antimicrobial therapy and de-escalation are routinely practiced without the use of infective biomarkers. Crystalloids are preferred over colloids for the initial resuscitation. CVPs and fluid challenges are still preferred over the new fluid responsiveness methods for preload assessment. Hydrocortisone is the most common steroid prescribed for septic shock but the threshold of initiation, frequency of use and methods of discontinuation vary.


Ultrastructure of the leptomeninx of the fetal ferret spinal cord and cerebrum.
The ultrastructures of the leptomeninx of the spinal cord and cerebrum was examined in the 32 d post-conception fetal ferret. Leptomeningeal cells of the fetal ferret spinal cord have a moderately electron dense cytoplasm and nucleoplasm. The cisternae of endoplasmic reticulum are filled with an amorphous material and are more numerous in cells covering the lateral part of the cord. Collagen fibrils are also abundant in this region. Glycogen granules are only rarely present and then only in arachnoid cells. Cells of the cerebral leptomenix have a much less electron dense cytoplasm and nucleoplasm and glycogen is present in most cells, sparsely scattered in pial cells, but more plentiful in arachnoid cells. Collagen fibrils are much less numerous and of a finer diameter than those found in the spinal leptomeninx. Cells of the spinal leptomeninx are therefore at a more advanced stage of differentiation than those of the cerebral leptomeninx.


Serology in leprosy.
A critical survey of the literature on serology in leprosy has shown that sera taken from lepromatous patients display some striking differences in comparison with sera from tuberculoid patients. The tests most frequently employed were complement-fixation, haemagglutination, electrophoresis, precipitation and immunofluorescence, together with a variety of antigens not only from lepromas but also from Mycobacterium tuberculosis and other actinomycetales.With the exception of the Rubino test, all these serological tests are lacking in specificity for leprosy since leprous sera have a broad range of reactivity with different antigens, including those employed in the serological diagnosis of syphilis.Some features of the leprous sera could be related to a hypersensitivity state involving circulating immune complexes, low levels of complement and the presence of antibodies similar to those found in sera from patients with autoimmune diseases.


Expression of matrix metalloproteases (MMP-2, MT1 -MMP) and their tissue inhibitor (TIMP-2) by rat sertoli cells in culture: implications for spermatogenesis.
During testicular development and maturation, extracellular matrix (ECM) remodelling is a fundamental process which requires the presence of several proteases and protease inhibitors. Among the proteases, a pivotal role has been proposed for matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs). Here we report an analysis of MMP-2, MT1-MMP and TIMP-2 expression by rat Sertoli cells in culture using RT-PCR and zymographic techniques. Stimulating Sertoli cells with follicle-stimulating hormone (FSH) in vitro induced evident changes in the level of their mRNA in a time-dependent manner. In the case of TIMP-2 and MT1-MMP, the respective transcripts were augmented up to three-fold after 24 h of treatment, and MMP-2 transcripts increased by four times in the same period. MMP-2 activity determined by gelatin zymography showed an increase in enzyme secretion after FSH stimulation. The results of this study suggest that: (i) at the surface of Sertoli cells pro-MMP-2 activation mediated by MT1-MMP may occur, involving TIMP-2 as a receptor; and (ii) the expression of these molecules is not constitutive in this cell type, but may be modulated by FSH and is therefore implicated in spermatogenesis.


Circadian gene expression in mammalian fibroblasts revealed by real-time luminescence reporting: temperature compensation and damping.
Mammalian cells such as rat-1 fibroblasts have been shown to exhibit daily oscillations in the expression of several gene transcripts in culture. After induction, these oscillations persist with a period of approximately 24 h for several days. This characteristic suggests that the oscillations are controlled by a circadian clock, but the crucial criterion of temperature compensation has not been demonstrated for rat-1 fibroblasts. We have developed an automated assay of circadian expression of the mPer1 promoter in rat-1 fibroblasts that have been stably transfected with a luciferase reporter. Using this cell culture-based in vitro luminescent reporter assay, we found that the daily oscillation of mPer1 promoter activity in rat-1 cells is temperature compensated over the range of 28.5-36.5 degrees C. This finding means that these oscillations are bona fide circadian rhythms. Moreover, the circadian clock of these homeothermic mammalian cells not only is temperature compensated but also is overcompensated such that it runs faster at cooler temperatures (Q10 of 0.85-0.88). The oscillations in rat-1 fibroblasts damp more rapidly at cooler temperatures, and damping is not due to cells becoming unhealthy because a second stimulus will reinitiate a robust rhythm. These data show that rat-1 cell cultures that are stably transfected with luminescence reporters are an excellent model system for studying circadian clocks at the cellular level in mammals.


Brittle Dyskinesia Following STN but not GPi Deep Brain Stimulation.
The aim was to describe the prevalence and characteristics of difficult to manage dyskinesia associated with subthalamic nucleus (STN) deep brain stimulation (DBS). A small subset of STN DBS patients experience troublesome dyskinesia despite optimal programming and medication adjustments. This group of patients has been referred to by some practitioners as brittle STN DBS-induced dyskinesia, drawing on comparisons with brittle diabetics experiencing severe blood sugar regulation issues and on a single description by McLellan in 1982. We sought to describe, and also to investigate how often the "brittle" phenomenon occurs in a relatively large DBS practice. An Institutional Review Board-approved patient database was reviewed, and all STN and globus pallidus internus (GPi) DBS patients who had surgery at the University of Florida from July 2002 to July 2012 were extracted for analysis. There were 179 total STN DBS patients and, of those, four STN DBS (2.2%) cases were identified as having dyskinesia that could not be managed without the induction of an "off state," or by the precipitation of a severe dyskinesia despite vigorous stimulation and medication adjustments. Of 75 GPi DBS cases reviewed, none (0%) was identified as having brittle dyskinesia. One STN DBS patient was successfully rescued by bilateral GPi DBS. Understanding the potential risk factors for postoperative troublesome and brittle dyskinesia may have an impact on the initial surgical target selection (STN vs. GPI) in DBS therapy. Rescue GPi DBS therapy may be a viable treatment option, though more cases will be required to verify this observation.


Implications of GLAGOV study.
Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition has emerged as a novel approach to lowering levels of low-density lipoprotein cholesterol (LDL-C). The impact of PCSK9 inhibition in statin-treated patients on coronary atherosclerosis had remained unknown. The GLAGOV trial compared the effect of the PCSK9 inhibitor, evolocumab, and placebo on progression of coronary atherosclerosis in patients treated with at least moderate intensity statin therapy. Predictable lowering of LDL-C with evolocumab (36.6 versus 93.0 mg/dl) associated with significant regression of coronary atherosclerosis. A direct relationship was observed between achieved LDL-C levels and disease progression. Addition of evolocumab to statin therapy produces incremental regression of plaque regression in patients with established coronary artery disease. This finding provides a biological rationale for the reported beneficial effects of evolocumab on cardiovascular events.


Robotic-Assisted DIEP Flap Harvest for Autologous Breast Reconstruction: A Comparative Feasibility Study on a Cadaveric Model.
The deep inferior epigastric perforator (DIEP) flap is the most common perforator flap for microsurgical breast reconstruction. Contrary to the conventional open approach, robotic-assisted DIEP flap harvest intends to preserve ARS integrity, thereby reducing the morbidity. We assessed the feasibility and compared performance outcomes of a robotic, cadaveric training model for DIEP flap harvest using two approaches: transabdominal preperitoneal (TAPP) and totally extraperitoneal (TEP). A robotics system (da Vinci Xi) was applied in conjunction with a cadaveric training model. Ports were placed in the abdominal wall to triangulate each DIEP flap. Surgical time and technical characteristics were recorded. Values were analyzed and compared. Eight female cadavers (16 hemi-DIEP flaps) were dissected: 50% TAPP and 50% TEP approaches. Mean harvest time was 56 minutes (range: 48-74 minutes) and 65 minutes (range: 60-83 minutes) for TAPP versus TEP groups, respectively (p < 0.05). Mean pedicle dissection time was 36 minutes (range: 25-40 minutes) and 39 minutes (range: 30-42 minutes) for TAPP versus TEP groups, respectively (p > 0.05). Intra-abdominal contents were manipulated twice on average in the TAPP group versus 0 times in the TEP group (p < 0.05). One TAPP case had an injury to the bowel, and one TEP case was converted to conventional open due to pneumoperitoneum. Robotic-assisted DIEP flap harvest represents a technological enhancement for advanced regenerative plastic surgery. Our model demonstrated both TAPP and TEP are feasible, with TEP less invasive, preserving the posterior rectus sheath, and decreasing complication risks. However, there is a steeper and longer learning curve for TEP.


Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial.
Activated protein C (APC) resistance not related to the factor V Leiden mutation is a risk factor for venous thrombosis. Oral estrogen replacement therapy (ERT) has been reported to induce APC resistance. Little is known about the effect of transdermal estrogen. We enrolled 196 postmenopausal women who were randomly allocated to receive either 1 mg 17beta-estradiol orally (n=63) or 50 microg 17beta-estradiol transdermally per day (n=68), both associated with 100 mg progesterone daily or placebo (n=65) for 6 months. An activated partial thromboplastin time (APTT)-based test and the effect of APC on thrombin potential (ETP) were used. Oral ERT induced an ETP-based APC resistance compared with both placebo (P=0.006) and transdermal ERT (P<0.001), but there was no significant effect of transdermal ERT compared with placebo (P=0.191). There was no significant effect of ERT on the APTT-based APC sensitivity ratio. Prothrombin fragment 1+2 plasma levels were significantly higher after 6 months of treatment in women allocated to oral ERT compared with those on placebo and transdermal ERT and were positively and significantly correlated with changes in ETP-based APC sensitivity ratio. Our data show that oral, unlike transdermal, estrogen induces APC resistance and activates blood coagulation. These results emphasize the importance of the route of estrogen administration.


Measuring the Needs of Family Caregivers of People With Dementia: An Assessment of Current Methodological Strategies and Key Recommendations.
While dementia caregivers are regarded as a population with high unmet needs, there is little consensus as to how caregivers' needs should be conceptualized and measured. This article describes how dementia caregivers' needs are currently assessed in the scientific literature with the goal of suggesting guidelines for the enhancement of future measurement of caregiver needs. A review of 26 articles identified overarching themes within measurement approaches including variation in methodological rigor, proxy indicators of need, dual needs assessment of caregiver and person with dementia (PWD), and third-party needs assessment. We recommend future research dedicate theoretical attention to the conceptualization and classification of caregivers' needs to build a stronger foundation for measurement. The measurement development process should capitalize on mixed-methodology and follow instrument development and validation guidelines set forth by measurement theory. Reliable and valid instruments are essential to developing services and policies that address dementia caregivers' needs.


Hypothalamic function as related to body weight and body fat in anorexia nervosa.
Percentage body fat is predictive of the onset of menstruation at puberty. In anorexia nervosa a relationship between luteinizing hormone (LH) levels and percentage weight loss has been reported. In the current study the relationship of percentage body fat and of percentage weight loss to LH and LH reactivity was examined in anorexia nervosa. Fifteen women with anorexia nervosa were studied. The resting levels of LH were measured, and in seven of the subjects LH response to luteinizing hormone releasing hormone (LHRH) and clomiphene was tested. The increment in plasma LH was measured in response to a 100 microgram dose of LHRH, and also to a 5-day course of clomiphene 100 mg. The resting LH levels were found to correlate with percentage fat, body weight, and percentage weight loss. Correlations were also found between the response to either LHRH or clomiphene and percentage weight loss, percentage fat, and absolute body weight. Other pituitary hormones measured did not show a relationship to body fat or weight. It is concluded that in addition to being predictive of the onset of menstruation, percentage body fat is significantly related to resting LH and LH reactivity in anorexia nervosa. Although percentage body fat, percentage weight loss, and absolute body weight are all significant correlates of LH reactivity, we cannot at this time conclude that any one in particular is the superior.


Bällchen is required for self-renewal of germline stem cells in Drosophila melanogaster.
Self-renewing stem cells are pools of undifferentiated cells, which are maintained in cellular niche environments by distinct tissue-specific signalling pathways. In Drosophila melanogaster, female germline stem cells (GSCs) are maintained in a somatic niche of the gonads by BMP signalling. Here we report a novel function of the Drosophila kinase Bällchen (BALL), showing that its cell autonomous role is to maintain the self-renewing capacity of female GSCs independent of BMP signalling. ball mutant GSCs are eliminated from the niche and subsequently differentiate into mature eggs, indicating that BALL is largely dispensable for differentiation. Similar to female GSCs, BALL is required to maintain self-renewal of male GSCs, suggesting a tissue independent requirement of BALL for self-renewal of germline stem cells.


Integrative Multianalytical Model Based on Novel Plasma Protein Biomarkers for Distinguishing Lung Adenocarcinoma and Benign Pulmonary Nodules.
Given the pressing clinical problem of making a decision in diagnosis for subjects with pulmonary nodules, we aimed to discover novel plasma protein biomarkers for lung adenocarcinoma (LUAD) and benign pulmonary nodules (BPNs) and then develop an integrative multianalytical model to guide the clinical management of LUAD and BPN patients. Through label-free quantitative plasma proteomic analysis (data are available via ProteomeXchange with identifier PXD046731), 12 differentially expressed proteins (DEPs) in LUAD and BPN were screened. The diagnostic abilities of DEPs were validated in two independent validation cohorts. The results showed that the levels of three candidate proteins (PRDX2, PON1, and APOC3) were lower in the plasma of LUAD than in BPN. The three candidate proteins were combined with three promising computed tomography indicators (spiculation, vascular notch sign, and lobulation) and three traditional markers (CEA, CA125, and CYFRA21-1) to construct an integrative multianalytical model, which was effective in distinguishing LUAD from BPN, with an AUC of 0.904, a sensitivity of 81.44%, and a specificity of 90.14%. Moreover, the model possessed impressive diagnostic performance between early LUADs and BPNs, with the AUC, sensitivity, specificity, and accuracy of 0.868, 65.63%, 90.14%, and 82.52%, respectively. This model may be a useful auxiliary diagnostic tool for LUAD and BPN by achieving a better balance of sensitivity and specificity.


Intravenously Administered Ganaxolone Blocks Diazepam-Resistant Lithium-Pilocarpine-Induced Status Epilepticus in Rats: Comparison with Allopregnanolone.
Ganaxolone (GNX) is the 3β-methylated synthetic analog of the naturally occurring neurosteroid, allopregnanolone (ALLO). GNX is effective in a broad range of epilepsy and behavioral animal models and is currently in clinical trials designed to assess its anticonvulsant and antidepressant activities. The current studies were designed to broaden the anticonvulsant profile of GNX by evaluating its potential anticonvulsant activities following i.v. administration in treatment-resistant models of status epilepticus (SE), to establish a pharmacokinetic (PK)/pharmacodynamic (PD) relationship, and to compare its PK and anticonvulsant activities to ALLO. In PK studies, GNX had higher exposure levels, a longer half-life, slower clearance, and higher brain penetrance than ALLO. Both GNX and ALLO produced a sedating response as characterized by loss of righting reflex, but neither compound produced a full anesthetic response as animals still responded to painful stimuli. Consistent with their respective PK properties, the sedative effect of GNX was longer than that of ALLO. Unlike other nonanesthetizing anticonvulsant agents indicated for SE, both GNX and ALLO produced anticonvulsant activity in models of pharmacoresistant SE with administration delay times of up to 1 hour after seizure onset. Again, consistent with their respective PK properties, GNX produced a significantly longer anticonvulsant response. These studies show that GNX exhibited improved pharmacological characteristics versus other agents used as treatments for SE and position GNX as a uniquely acting treatment of this indication.


Effects of flow rate and insulin on triacylglycerol secretion by perfused rat liver.
In rat livers perfused with undiluted rat blood at perfusion rates of 6, 12, or 18 ml/min, hepatic O2 consumption rose with blood flow. Lipogenesis was unaffected by blood flow in control livers and was enhanced by insulin at 12 and 18 ml/min. Very-low-density lipoprotein triacylglycerol secretion also rose with increased flow and was stimulated by insulin at both 6 and 12 ml/min. When glucose was added to livers perfused at 12 or 18 ml/min, uptake was independent of perfusion rate and was slightly stimulated by insulin. Total lipogenesis and the secretion of newly synthesized fatty acids in very-low-density lipoprotein triacylglycerols were unaffected by insulin at either flow rate. The hormone stimulated triacylglycerol secretion at 18 ml/min but inhibited it at 12 ml/min. It seems that in perfused liver, effects of insulin on lipogenesis and very-low-density lipoprotein secretion may be modified not only by changes in O2 consumption (in this case through alterations in blood flow) but also by the choice of substrate.


Thermally activated delayed fluorescence in a deep red dinuclear iridium(iii) complex: a hidden mechanism for short luminescence lifetimes.
The high luminescence efficiency of cyclometallated iridium(iii) complexes, including those widely used in OLEDs, is typically attributed solely to the formally spin-forbidden phosphorescence process being facilitated by spin-orbit coupling with the Ir(iii) centre. In this work, we provide unequivocal evidence that an additional mechanism can also participate, namely a thermally activated delayed fluorescence (TADF) pathway. TADF is well-established in other materials, including in purely organic compounds, but has never been observed in iridium complexes. Our findings may transform the design of iridium(iii) complexes by including an additional, faster fluorescent radiative decay pathway. We discover it here in a new dinuclear complex, 1, of the form [Ir(N^C)2]2(μ-L), where N^C represents a conventional N^C-cyclometallating ligand, and L is a bis-N^O-chelating bridging ligand derived from 4,6-bis(2-hydroxyphenyl)-pyrimidine. Complex 1 forms selectively as the rac diastereoisomer upon reaction of [Ir(N^C)2(μ-Cl)]2 with H2L under mild conditions, with none of the alternative meso isomer being separated. Its structure is confirmed by X-ray diffraction. Complex 1 displays deep-red luminescence in solution or in polystyrene film at room temperature (λem = 643 nm). Variable-temperature emission spectroscopy uncovers the TADF pathway, involving the thermally activated re-population of S1 from T1. At room temperature, TADF reduces the photoluminescence lifetime in film by a factor of around 2, to 1 μs. The TADF pathway is associated with a small S1-T1 energy gap ΔEST of approximately 50 meV. Calculations that take into account the splitting of the T1 sublevels through spin-orbit coupling perfectly reproduce the experimentally observed temperature-dependence of the lifetime over the range 20-300K. A solution-processed OLED comprising 1 doped into the emitting layer at 5 wt% displays red electroluminescence, λEL = 625 nm, with an EQE of 5.5% and maximum luminance of 6300 cd m-2.


Pro-invasive activity of the Hippo pathway effectors YAP and TAZ in cutaneous melanoma.
YAP and its paralog protein TAZ are downstream effectors of the Hippo pathway. Both are amplified in many human cancers and promote cell proliferation and epithelial-mesenchymal transition. Little is known about the status of the Hippo pathway in cutaneous melanoma. We profiled Hippo pathway component expression in a panel of human melanoma cell lines and melanocytic lesions, and characterized the capacity of YAP and TAZ to control melanoma cell behavior. YAP and TAZ immuno-staining in human samples revealed mixed cytoplasmic and nuclear staining for both proteins in benign nevi and superficial spreading melanoma. TAZ was expressed at higher levels than YAP1/2 in all cell lines and in those with high invasive potential. Stable YAP or TAZ knockdown dramatically reduced the expression of the classical Hippo target CCN2/connective-tissue growth factor (CTGF), as well as anchorage-independent growth, capacity to invade Matrigel, and ability form lung metastases in mice following tail-vein injection. YAP knockdown also reduced invasion in a model of skin reconstruct. Inversely, YAP overexpression increased melanoma cell invasiveness, associated with increased TEA domain-dependent transcription and CCN2/CTGF expression. Together, these results demonstrate that both YAP and TAZ contribute to the invasive and metastatic capacity of melanoma cells and may represent worthy targets for therapeutic intervention.


Safety and effectiveness of radiologic and endoscopic percutaneous gastrostomy placement: A randomized study.
Gastrostomy tubes placed radiologically, endoscopically or surgically facilitate long-term home enteral nutrition (HEN). Patient-specific clinical factors may affect placement techniques, confounding direct comparisons between radiologically inserted gastrostomy (RIG) and percutaneous endoscopic gastrostomy (PEG) outcomes. This study sought to evaluate the differences in clinical outcomes in patients undergoing gastrostomy tube placement by interventional radiologists or gastroenterologists. A single-center prospective trial randomizing patients initiating HEN to RIG or PEG was conducted between March 2018 and June 2021. Patients were followed until the time of gastrostomy removal or until 9 months after tube placement. Tracked complications included peritonitis, abscess, bleeding, bowel perforation, and tube occlusion, malposition, or damage. Periprocedural pain rating and quality of life (QoL) surveys were collected. Forty-two patients were randomized to RIG or PEG. Twenty patients underwent RIG (mean age, 63.0 ± 11.7 years; 85% male; 95% with head and neck cancer) and 22 patients underwent PEG (mean age, 66.3 ± 10.9 years; 81.8% male; 90.9% with head and neck cancer). RIG and PEG groups had 4.18 ± 5.49 and 2.80 ± 5.82 complications per 1000 HEN days, respectively (P = 0.357). The most frequent complications were tube malposition and abscess formation for the RIG and PEG groups, respectively. No major complications occurred in either group. There was no difference in the average of pain ratings in all pain inventory components across both groups. Both groups reported improvement in overall QoL after gastrostomy tube placement (P = 0.532). RIG is noninferior to PEG regarding complication rates, pain, and QoL when compared in a prospective randomized fashion.


Mismatch of neurophysiological findings in partial recovery of consciousness: a case report.
Electroencephalography (EEG) and somatosensory potentials (SEP) are regarded as useful tools for exploring residual brain activity and providing information for recovery in patients with anoxic encephalopaty. However, the diagnoses of vegetative and minimally conscious states can only be made by means of repeated specific neurological examinations. In this respect, this study describes the case of a patient with mismatch of neurophysiological findings despite partial recovery to a minimally conscious state. A 52-year-old man was admitted to the Post-Coma Intensive and Rehabilitation Care Unit with a diagnosis of anoxic encephalopathy. EEG, according to Hockaday, was severely abnormal (Grade IVa). SEP showed bilateral loss of all cortical components. Four weeks after admission the Coma Recovery Scale Revised (CRS-R) score moved from 7/23 to 13/23. This patient persistently showed a mismatch of neurophysiological findings which did not anticipate the slight but discriminating improvement ascertained through the neurological examination. This observation confirms that electrophysiological evaluations can only be regarded as ancillary tools since level of consciousness may be reliably evaluated only by means of repeated specific neurological assessments. As this case-report suggests, neurophysiological findings may turn out to be inconclusive and misleading in relation to the assessment of consciousness and may lead to an underestimate of minimal signs of recovery across the grey-zone from the vegetative to the minimally conscious state.


Prevalence of Vestibular Disorder in Older People Who Experience Dizziness.
Dizziness and imbalance are clinically poorly defined terms, which affect ~30% of people over 65 years of age. In these people, it is often difficult to define the primary cause of dizziness, as it can stem from cardiovascular, vestibular, psychological, and neuromuscular causes. However, identification of the primary cause is vital in determining the most effective treatment strategy for a patient. Our aim is to accurately identify the prevalence of benign paroxysmal positional vertigo (BPPV), peripheral, and central vestibular hypofunction in people aged over 50 years who had experienced dizziness within the past year. Seventy-six participants aged 51-92 (mean ± SD = 69 ± 9.5 years) were tested using the head thrust dynamic visual acuity (htDVA) test, dizziness handicap inventory (DHI), as well as sinusoidal and unidirectional rotational chair testing, in order to obtain data for htDVA score, DHI score, sinusoidal (whole-body, 0.1-2 Hz with peak velocity at 30°/s) vestibulo-ocular reflex (VOR) gain and phase, transient (whole-body, acceleration at 150°/s(2) to a constant velocity rotation of 50°/s) VOR gain and time constant (TC), optokinetic nystagmus (OKN) gain, and TC (whole-body, constant velocity rotation at 50°/s). We found that BPPV, peripheral and central vestibular hypofunction were present in 38 and 1% of participants, respectively, suggesting a likely vestibular cause of dizziness in these people. Of those with a likely vestibular cause, 63% had BPPV; a figure higher than previously reported in dizziness clinics of ~25%. Our results indicate that htDVA, sinusoidal (particularly 0.5-1 Hz), and transient VOR testing were the most effective at detecting people with BPPV or vestibular hypofunction, whereas DHI and OKN were effective at only detecting non-BPPV vestibular hypofunction.


Use of the INNO-LiPA-MYCOBACTERIA assay (version 2) for identification of Mycobacterium avium-Mycobacterium intracellulare-Mycobacterium scrofulaceum complex isolates.
Using INNO-LiPA-MYCOBACTERIA (Lipav1; Innogenetics) and the AccuProbe (Gen-Probe Inc./bioMérieux) techniques, 35 Mycobacterium avium-Mycobacterium intracellulare-Mycobacterium scrofulaceum (MAC/MAIS) complex strains were identified between January 2000 and December 2002. Thirty-four of 35 isolates were positive only for the MAIS complex probe by Lipav1 and were further analyzed by INNO-LiPA-MYCOBACTERIA version 2 (Lipav2), hsp65 PCR restriction pattern analysis (PRA), and ribosomal internal transcribed spacer (ITS), hsp65, and 16S rRNA sequences. Lipav2 identified 14 of 34 strains at the species level, including 11 isolates positive for the newly specific MAC sequevar Mac-A probe (MIN-2 probe). Ten of these 11 isolates corresponded to sequevar Mac-A, which was recently defined as Mycobacterium chimerae sp. nov. Among the last 20 of the 34 MAIS isolates, 17 (by hsp65 PRA) and 18 (by hsp65 sequence) were characterized as M. avium. Ten of the 20 were identified as Mac-U sequevar. All these 20 isolates were identified as M. intracellulare by 16S rRNA sequence except one isolate identified as Mycobacterium paraffinicum by 16S rRNA and ITS sequencing. One isolate out of 35 isolates that was positive for M. avium by AccuProbe and that was Mycobacterium genus probe positive and MAIS probe negative by Lipav1 and Lipav2 might be considered a new species. In conclusion, the new INNO-LiPA-MYCOBACTERIA allowed the identification of 40% of the previously unidentified MAIS isolates at the species level. The results of the Lipav2 assay on the MAIS isolates confirm the great heterogeneity of this group and suggest the use of hsp65 or ITS sequencing for precise identification of such isolates.


Sleep Duration across the Adult Lifecourse and Risk of Lung Cancer Mortality: A Cohort Study in Xuanwei, China.
Sufficient sleep duration is crucial for maintaining normal physiological function and has been linked to cancer risk; however, its contribution to lung cancer mortality is unclear. Therefore, we evaluated the relationship between average sleep duration in various age-periods across the adult lifecourse, and risk of lung cancer mortality in Xuanwei, China. An ambidirectional cohort study was conducted in 42,422 farmers from Xuanwei, China. Participants or their surrogates were interviewed in 1992 to assess average sleep hours in the age periods of 21-30, 31-40, 41-50, 51-60, 61-70, and ≥71 years, which were categorized as ≤7, 8 (reference), 9, and ≥10 hours/day. Vital status was followed until 2011. Sex-specific Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for lung cancer mortality in 1994-2011, adjusted for demographic, anthropometric, medical, and household characteristics. J-shaped relationships were found between average sleep duration and lung cancer mortality. The patterns were consistent across sex, age periods, and fuel usage. Compared with sleeping 8 hours/day on average, ≤7 hours/day was associated with significantly increased HRs ranging from 1.39 to 1.58 in ages ≥41 years in men, and 1.29 to 2.47 in ages ≥51 years in women. Furthermore, sleeping ≥10 hours/day was associated with significantly increased HRs ranging from 2.44 to 3.27 in ages ≥41 year in men, and 1.31 to 2.45 in ages ≤60 years in women. Greater and less than 8 hours/day of sleep in various age-periods may be associated with elevated risk of lung cancer mortality in Xuanwei, China. Cancer Prev Res; 10(6); 327-35. ©2017 AACR.


Involution of the mammalian thymus, one of the leading regulators of aging.
During the past century of research on the thymus, the fact that every mammalian thymus undergoes marked morphological changes during the complex process of aging has been defined as a basic histogenetical rule. In characterizing the physiological (i.e. chronic) involution of the mammalian thymus, the term "Altersinvolution" referring to age-related involution is used. All other types of thymic involution are associated with an initial trigger and a relatively "acute" mechanism. In all of these factor-dependent cases of thymic involution, we use the term "akzidentelle Involution" (i.e. acute accidental thymic involution). Temporary thymic involution occurs during pregnancy, with a full restoration of the cellular microenvironment at the end of lactation. It is now clear that pregnancy alters the well established adaptational homeostasis between the neuroendocrine and immune axes. Such nonprogressive involution has also been observed during various seasons in various animals (i.e. seasonal involution). Changes characteristic of thymic involution begin during or soon after the first year of birth, and continue progressively throughout the entire life span. The 3% to 5% annual reduction rate of the cells of the human thymic microenvironment continues until middle age, when it slows down to less than 1% per year. According to the extrapolation of these results total loss of thymic reticuloepithelial tissue and the associated thymocytes should occur only at the age of 120 years in humans. This serious reduction of the thymic cellular microenvironment is a well controlled physiological process and is presumably under both local and global regulation by the cells of the RE meshwork and the neuroendocrine system, respectively. In humans, the age related decline in serum "facteur thymique sérique" (FTS) levels begins after 20 years of age and FTS completely disappears from the blood between the 5th and 6th decade of life. In contrast, the serum levels of thymosin-alpha 1 and thymopoietin seem to decline earlier, starting as early as 10 years of age. The influences of a variety of other hormones on the involution of the thymus have also been characterized: testosterone, estrogen and hydrocortisone treatment results in marked involution, cortisone and progesterone administration causes slight to moderate, while use of desoxycorticosterone has no effect. The experimental administration of thyroxine yielded dose dependent results: low doses resulted in thymic hypertrophy, higher doses produced slight hypertrophy and the highest employed doses caused thymic atrophy. The atrophy was of apicnotic type, very different from that detected after treatment with corticoid hormones. Thymus transplantation experiments indicate that age-related, physiological thymic involution has been genetically preprogrammed. Grafting of the thymus from one week old C3H leukemic strain mice into 6 month old hosts resulted in changes in thymic weight and an involution pattern that was synchronous in all recipients, in direct correlation with the glands in the donor, but not in the host. These data strongly suggest that the stimulus for thymus cell proliferation and differentiation is genetically determined within the organ implant. Since the thymus is the primary T-lymphopoietic organ during ontogenesis in the mammalian organism, its age-related involution with the already mentioned morphological alterations can be held responsible only for a decline in antigen-specific T lymphocyte immune functions. Thymic involution and diminished T lymphocyte proliferation can be partially restored by thymic tissue transplantation or use of thymic hormones. The leading physiological role of the thymic cellular microenvironment as a "clock" of the mammalian aging process is also discussed. "If present cells have come from pre-existing cells, then all cells can trace their ancestry back to the first formed cell in an unbroken line of descent."--Rudolf Virchow, 1858(1) "I have neve


The final step in the phage infection cycle: the Rz and Rz1 lysis proteins link the inner and outer membranes.
Bacteriophage lambda has four adjacent genes -S, R, Rz and Rz1- dedicated to host cell lysis. While S, encoding the holin and antiholin, and R, encoding the endolysin, have been intensively studied, the products of Rz and Rz1 have not been characterized at either the structural or functional levels. Rz1 is an outer membrane lipoprotein and our results indicate that Rz is a type II signal anchor protein. Here we present evidence that an Rz-Rz1 complex that spans the periplasm carries out the final step in the process of host lysis. These results are discussed in terms of a model where endolysin-mediated degradation of the cell wall is a prerequisite for conformational changes in the Rz-Rz1 complex leading to the juxtaposition and fusion of the IM and OM. Fusion of the two membranes removes the last physical barrier to efficient release of progeny virions.


The efficacy of classical massage on stress perception and cortisol following primary treatment of breast cancer.
To investigate the efficacy of classical massage on stress perception and mood disturbances, 34 women diagnosed with primary breast cancer were randomized into an intervention or control group. For a period of 5 weeks, the intervention group (n = 17) received biweekly 30-min classical massages. The control group (n = 17) received no additional treatment to their routine health care. The Perceived Stress Questionnaire (PSQ) and the Berlin Mood Questionnaire (BSF) were used and the patients' blood was collected at baseline (T1), at the end of the intervention period (T2), and 6 weeks after T2 (T3). Compared with control group, women in the intervention group reported significantly lower mood disturbances, especially for anger (p = 0.048), anxious depression (p = 0.03) at T2, and tiredness at T3 (p = 0.01). No group differences were found in PSQ scales, cortisol and serotonin concentrations at T2 and T3. However, perceived stress and cortisol serum levels (p = 0.03) were significantly reduced after massage therapy (T2) compared with baseline in the intervention group. Further research is needed to validate our findings.


Segmentation of whole cells and cell nuclei from 3-D optical microscope images using dynamic programming.
Communications between cells in large part drive tissue development and function, as well as disease-related processes such as tumorigenesis. Understanding the mechanistic bases of these processes necessitates quantifying specific molecules in adjacent cells or cell nuclei of intact tissue. However, a major restriction on such analyses is the lack of an efficient method that correctly segments each object (cell or nucleus) from 3-D images of an intact tissue specimen. We report a highly reliable and accurate semi-automatic algorithmic method for segmenting fluorescence-labeled cells or nuclei from 3-D tissue images. Segmentation begins with semi-automatic, 2-D object delineation in a user-selected plane, using dynamic programming (DP) to locate the border with an accumulated intensity per unit length greater that any other possible border around the same object. Then the two surfaces of the object in planes above and below the selected plane are found using an algorithm that combines DP and combinatorial searching. Following segmentation, any perceived errors can be interactively corrected. Segmentation accuracy is not significantly affected by intermittent labeling of object surfaces, diffuse surfaces, or spurious signals away from surfaces. The unique strength of the segmentation method was demonstrated on a variety of biological tissue samples where all cells, including irregularly shaped cells, were accurately segmented based on visual inspection.


Facultative Heterotrophy in Some Chlorococcacean Algae.
All known species of the genera Bracteacoccus, Spongiochloris, and Dictyochloris, and some of the species of Neochloris and Spongiococcum are capable of growing heterotrophically in darkness in a glucose-salts medium. In contrast, all known species of Chlorococcum are obligate photoautotrophs. Possible relationships between these results and certain morphological characteristics are discussed.


Social network, political climate, income inequality, and Americans uptake of monovalent COVID-19 booster.
The COVID-19 pandemic has posed an unprecedented impact on Americans for over three years. To control the damage, a booster shot becomes increasingly necessary because the efficacy of the initial vaccine is waning and new variants of the virus are emerging. This study aims to understand factors at both individual and state levels that influence one's decision to take the monovalent booster. We merged data from a national survey administered in the Spring of 2022 with state-level indicators of the political climate, income inequality, and public health conditions. Multilevel logistic regression is adopted for statistical estimation. Findings show contrasting effects of the social network. More vaccinated people in one's network promote booster uptake, while more family members and close friends who contracted the virus in one's network inhibit booster uptake. In addition, residents of states with more votes for the Democratic candidate in the 2020 general election are more likely to take the booster. Meanwhile, residents from states with high income inequality are less likely to become boosted. This study identified multilevel determinants of the individual decision to receive the monovalent COVID-19 booster. The results imply the need to leverage the social network, weaken partisanship salience, and reduce income inequality to encourage booster uptake.


A Neurodevelopmental Shift in Reward Circuitry from Mother's to Nonfamilial Voices in Adolescence.
The social worlds of young children primarily revolve around parents and caregivers, who play a key role in guiding children's social and cognitive development. However, a hallmark of adolescence is a shift in orientation toward nonfamilial social targets, an adaptive process that prepares adolescents for their independence. Little is known regarding neurobiological signatures underlying changes in adolescents' social orientation. Using functional brain imaging of human voice processing in children and adolescents (ages 7-16), we demonstrate distinct neural signatures for mother's voice and nonfamilial voices across child and adolescent development in reward and social valuation systems, instantiated in nucleus accumbens and ventromedial prefrontal cortex. While younger children showed greater activity in these brain systems for mother's voice compared with nonfamilial voices, older adolescents showed the opposite effect with increased activity for nonfamilial compared with mother's voice. Findings uncover a critical role for reward and social valuative brain systems in the pronounced changes in adolescents' orientation toward nonfamilial social targets. Our approach provides a template for examining developmental shifts in social reward and motivation in individuals with pronounced social impairments, including adolescents with autism.SIGNIFICANCE STATEMENT Children's social worlds undergo a transformation during adolescence. While socialization in young children revolves around parents and caregivers, adolescence is characterized by a shift in social orientation toward nonfamilial social partners. Here we show that this shift is reflected in neural activity measured from reward processing regions in response to brief vocal samples. When younger children hear their mother's voice, reward processing regions show greater activity compared with when they hear nonfamilial, unfamiliar voices. Strikingly, older adolescents show the opposite effect, with increased activity for nonfamilial compared with mother's voice. Findings identify the brain basis of adolescents' switch in social orientation toward nonfamilial social partners and provides a template for understanding neurodevelopment in clinical populations with social and communication difficulties.


[Double-blind placebo-controlled trial of terazosine efficacy in patients with chronic abacterial prostatitis].
A double-blind placebo-controlled trial of teraosin efficacy (Kornam, Lek, Slovenia) was made in 51 patients with chronic abacterial prostatitis/chronic pelvic pain syndrome (CAP/CPPS) of category IIla according to NIH. All the patients were given a 2-week induction course of placebo followed by teraosin treatment (5 mg/day, n = 29) or placebo (n = 22) for 8 weeks. The participants of the study were followed up for 12 months. Pretreatment differences between the groups by NIH-CPSI system, symptoms frequency scale, leukocyte count of the prostate and uroflowmetry were insignificant. Teraosin and placebo patients showed a noticeable improvement (39.7 and 9.9% by symptoms frequency scale, respectively; by 36.4 and 6.6% by the linear scale, respectively). The drug reduced pain and dysuria, improved quality of life considerably (by 36.2%). Maximal urine flow accelerated by 22.96 and 10.01% in teraosin and placebo groups, respectively. Leukocyte count fell two-fold in the study group and lowered insignificantly in the placebo group. The recurrence-free interval was 25 and 9 weeks, respectively. Thus, teraosin monotherapy improves quality of life in CAP/CPPS patients, significantly relieves symptoms and prolongs recurrence-free interval vs placebo.


The association of renal impairment with all-cause and cardiovascular disease mortality.
Background. The prognostic value of reduced glomerular filtration rate (GFR) was examined in a community-based cohort of British women. Methods. Serum creatinine measurements were available for 90% (n = 3851) of a representative random sample of 4286 women aged 60-79 years. GFR was estimated using the Modification of Diet in Renal Disease equation. Hazard ratios (HR) were calculated using Cox regression with outcomes of all-cause and cardiovascular disease (CVD) mortality. Results. Eight hundred and thirty-two women (21.6%) had a GFR <60 ml/min/1.73 m(2). Over a median follow-up of 5.6 years, there were 318 deaths (100 CVD deaths). Women with GFR <60 ml/min/1.73 m(2) compared to all others showed only a borderline increased risk of all-cause mortality [HR 1.35 (95% confidence intervals: 0.99, 1.85)] and CVD mortality [1.34 (0.97, 1.85)]. Adjustment for conventional CVD risk factors had little impact. The association with CVD mortality was attenuated in women with pre-existing CVD [adjusted HR: 0.51 (0.24, 1.04)]. Only the subset of women without CVD at baseline were at risk for later CVD death [adjusted HR: 1.80 (1.13, 2.88)]. Conclusions. A substantial proportion of older British women have GFR <60 ml/min/1.73 m(2) without strong evidence for statistical association with all-cause mortality. The effect on CVD mortality is partly explained by existing CVD and its risk factors. GFR measurement appears only to play a useful role in the subset of older women without pre-existing CVD who are at higher risk of premature CVD death.


Broader criteria of undifferentiated connective tissue disease in idiopathic interstitial pneumonias.
Kinder et al. proposed a broader definition of undifferentiated connective tissue disease (UCTD) and reported that the entity of nonspecific interstitial pneumonia (NSIP) is a lung manifestation of this more broadly defined UCTD. However, a retrospective study did not support their findings and its clinical significance remains unclear. We prospectively evaluated the significance of this broadly defined UCTD in idiopathic interstitial pneumonias (IIPs) in consecutive patients with surgical lung biopsy. Patients were evaluated with a symptoms check list and underwent comprehensive serologic testing as screening for UCTD. Clinical characteristics, high-resolution CT images, lung biopsy specimens, serial FVC change, and survival were analyzed. Among 76 patients with IIPs, 24 patients (32%) fulfilled the UCTD criteria. Diagnosis of 24 patients with UCTD was usual interstitial pneumonia in 12 (50%), NSIP in 7 (29%), and unclassifiable interstitial lung disease (ILD) in 5 (21%). The diagnosis of 52 patients who did not have UCTD was idiopathic pulmonary fibrosis in 27 (52%), NSIP in 11 (21%), unclassifiable ILD in 13 (25%) and cryptogenic organizing pneumonia in 1 (2%). One-year and two-year FVC changes showed no significant difference between UCTD and non-UCTD, however, significant differences in FVC change were observed among histopathological diagnoses both in UCTD and in non-UCTD. In multivariate survival analysis, %FVC and histopathological UIP pattern were independent predictors for survival but UCTD diagnosis was not. A diagnosis of UCTD was not useful in discriminating NSIP or in predicting disease progression and prognosis in our cohort of IIPs. Histopathological UIP pattern was an independent predictor for mortality irrespective of a diagnosis of UCTD.


Receptor targeting and heterogeneity at interneuronal nicotinic cholinergic synapses in vivo.
Within a single neuron the correct targeting of the diverse neurotransmitter receptor types to discrete synaptic regions is crucial for proper function. However, the molecular mechanisms that underlie neuronal receptor clustering and targeting are still largely undefined. Here we report advances in defining the mechanisms that mediate nicotinic acetylcholine receptor (nAChR) targeting to interneuronal synapses. Recent in vivo studies have demonstrated that one subunit plays a critical role in the differentiation of nicotinic cholinergic synapses on vertebrate autonomic neurons. The major cytoplasmic loop of the alpha3 subunit targets specific nAChR subtypes to the synapse. In contrast, nAChR complexes that lack the alpha3 targeting domain are excluded and are perisynaptic. Additional studies have demonstrated a greater complexity to alpha3-nAChR targeting due to a unique postsynaptic receptor microheterogeneity - under one presynaptic terminal, alpha3-nAChR clusters are separate, but proximal to, glycine receptor (GlyR) clusters in discrete postsynaptic membrane microregions. The surprising coexistence under one nerve ending of separate clusters of receptors that respond to different fast-acting transmitters with opposing functions may represent a novel mechanism for modulating synaptic activity. Overall, the receptor targeting and clustering studies reviewed in this issue suggest that a common mechanism underlies the formation of the diverse types of interneuronal synapses but differs from that responsible for neuromuscular junction assembly in vertebrates.


Cardiovascular risk score associations with frailty in men and women with or at risk for HIV.
To understand the relationship between cardiovascular disease (CVD) risk and frailty among men (MWH) and women living with HIV (WWH), or at risk for HIV. We considered 10-year coronary heart disease and atherosclerotic CVD risk by Framingham risk score (FRS, 2001 National Cholesterol Education Program Adult Treatment Program III) and Pooled Cohort Equations (PCE, 2013 American College of Cardiology/American Heart Association) in relation to the Fried Frailty Phenotype (FFP) in the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS). FFP was ascertained in MACS from 2004 to 2019 and in WIHS from 2005 to 2006 and 2011-2019. FFP score at least three of five components defined frailty. Repeated measures logistic regression (both cohorts) and Cox proportional hazards regression (MACS) were performed, controlled for education, income, cholesterol medication and hepatitis C virus serostatus, and among MWH and WWH, CD4+ cell count/μl, antiretroviral therapy, and HIV viral load. There were 5554 participants (1265 HIV seronegative/1396 MWH; 768 seronegative/1924 WWH) included. Among men, high-risk FRS was associated with increased risk of incident frailty among seronegative [adjusted hazard ratio (aHR)) = 2.12, 95% confidence interval (CI):1.22-3.69] and MWH (aHR = 2.19, 95% CI: 1.33-3.61). Similar associations were seen with high-risk PCE and incident frailty among SN (aHR = 1.88, 95% CI: 1.48-2.39) and MWH (aHR = 1.59, 95% CI: 1.26-2.00). Among women, high-risk PCE was associated with frailty in SN [adjusted odds ratio (aOR) = 1.43, 95% CI: 1.02-2.00] and WWH (aOR = 1.36, 95% CI: 1.08-1.71); however, high-risk FRS was not (seronegative: aOR = 1.03, 95% CI: 0.30-3.49; WWH: aOR = 0.86, 95% CI: 0.23-3.20). Higher CVD risk was associated with increased frailty regardless of HIV serostatus among men and women. These findings may inform clinical practices of screening for frailty.


Longitudinal PET imaging of tumor hypoxia during the course of radiotherapy.
Hypoxia results from an imbalance between oxygen supply and consumption. It is a common phenomenon in solid malignant tumors such as head and neck cancer. As hypoxic cells are more resistant to therapy, tumor hypoxia is an indicator for poor prognosis. Several techniques have been developed to measure tissue oxygenation. These are the Eppendorf O2 polarographic needle electrode, immunohistochemical analysis of endogenous (e.g., hypoxia-inducible factor-1α (HIF-1a)) and exogenous markers (e.g., pimonidazole) as well as imaging methods such as functional magnetic resonance imaging (e.g., blood oxygen level dependent (BOLD) imaging, T1-weighted imaging) and hypoxia positron emission tomography (PET). Among the imaging modalities, only PET is sufficiently validated to detect hypoxia for clinical use. Hypoxia PET tracers include 18F-fluoromisonidazole (FMISO), the most commonly used hypoxic marker, 18F-flouroazomycin arabinoside (FAZA), 18Ffluoroerythronitroimidazole (FETNIM), 18F-2-nitroimidazolpentafluoropropylacetamide (EF5) and 18F-flortanidazole (HX4). As technical development provides the opportunity to increase the radiation dose to subregions of the tumor, such as hypoxic areas, it has to be ensured that these regions are stable not only from imaging to treatment but also through the course of radiotherapy. The aim of this review is therefore to characterize the behavior of tumor hypoxia during radiotherapy for the whole tumor and for subregions by using hypoxia PET tracers, with focus on head and neck cancer patients.


Comprehensive Study on Solomonamides: Total Synthesis, Stereochemical Revision, and SAR Studies toward Identification of Simplified Lead.
Solomonamides, a pair of macrocyclic peptide natural products originating from marine sources, have garnered significant attention within the synthetic community owing to their marked anti-inflammatory efficacy and intricate molecular architectures. In this paper, we present a very detailed investigation into solomonamides, including the challenges associated with the total synthesis, the evolution of our synthetic strategies, structural reassignment, synthesis of all possible stereoisomeric macrocycles, biological assessment, structure-activity relationship (SAR) studies, etc. Within the ambit of this total synthesis, diverse strategies for macrocyclization were rigorously explored, encompassing the Friedel-Crafts acylation, cyclization involving the aniline NH2 moiety, macrolactamization utilizing Gly-NH2, and Heck macrocyclization methodologies. In addition, an array of intriguing chemical transformations were devised, including but not limited to photo-Fries rearrangement, Wacker oxidation, ligand-free Heck macrocyclization, oxidative cleavage of indole, synthesis of contiguous stereocenters via substrate/reagent-controlled protocols, and simultaneous making and breaking of olefinic moieties. The findings of this investigation revealed a structurally simplified lead compound. Remarkably, the lead compound, while possessing structural simplification in comparison to the intricate solomonamide counterparts, demonstrates equipotent in vivo anti-inflammatory efficacy.


Prevalence and Socio-Demographic Correlates of Poor Mental Health Among Older Adults in Agricultural Areas of China.
Objective: Poor mental health is associated with impaired social functioning, lower quality of life, and increased risk of suicide and mortality. This study examined the prevalence of poor general mental health among older adults (aged 65 years and above) and its sociodemographic correlates in Hebei province, which is a predominantly agricultural area of China. Methods: This epidemiological survey was conducted from April to August 2016. General mental health status was assessed using the 12-item General Health Questionnaire (GHQ-12). Results: A total of 3,911 participants were included. The prevalence of poor mental health (defined as GHQ-12 total score ≥ 4) was 9.31% [95% confidence interval (CI): 8.4-10.2%]. Multivariable logistic regression analyses found that female gender [P < 0.001, odds ratio (OR) = 1.63, 95% CI: 1.29-2.07], lower education level (P = 0.048, OR = 1.33, 95% CI: 1.00-1.75), lower annual household income (P = 0.005, OR = 1.72, 95% CI: 1.17-2.51), presence of major medical conditions (P < 0.001, OR = 2.95, 95% CI: 2.19-3.96) and family history of psychiatric disorders (P < 0.001, OR = 3.53, 95% CI: 2.02-6.17) were significantly associated with poor mental health. Conclusion: The prevalence of poor mental health among older adults in a predominantly agricultural area was lower than findings from many other countries and areas in China. However, continued surveillance of mental health status among older adults in China is still needed.


A rob-like gene of Enterobacter cloacae affecting porin synthesis and susceptibility to multiple antibiotics.
A chromosomal gene of Enterobacter cloacae affecting the synthesis of major outer membrane proteins in E. cloacae and Escherichia coli was cloned by using selection for resistance to cefoxitin in E. coli. The presence of the gene, when plasmid-borne, led to a decrease in the amount of porin F in E. cloacae and the amount of OmpF in E. coli and caused 2- to 32-fold increases in the MICs of chloramphenicol, tetracycline, quinolones, and beta-lactam antibiotics. The gene encoded a 33-kDa protein, similar (83% identity) to the protein Rob involved in the initiation of DNA replication in E. coli, which was called RobA(EC1) by analogy. RobA from E. cloacae was found to inhibit ompF expression at the posttranscriptional level via activation of micF, a gene also apparently present in E. cloacae, as detected by PCR. As with its homolog from E. coli, RobA(EC1) is related to the XylS-AraC class of positive transcriptional regulators, along with MarA and SoxS, which also cause a micF-mediated decrease in the level of ampF expression.


"Signaling when no one is watching: A reputation heuristics account of outrage and punishment In one-shot anonymous interactions": Correction to Jordan and Rand (2019).
Reports an error in "Signaling when no one is watching: A reputation heuristics account of outrage and punishment in one-shot anonymous interactions" by Jillian J. Jordan and David G. Rand (Journal of Personality and Social Psychology, Advanced Online Publication, Apr 15, 2019, np). In the article, a printer error did not enable the authors to correct various errors before publication. Tables 1 and 2 have been corrected. All versions of this article have been corrected. (The following abstract of the original article appeared in record 2019-20336-001.) Moralistic punishment can confer reputation benefits by signaling trustworthiness to observers. However, why do people punish even when nobody is watching? We argue that people often rely on the heuristic that reputation is typically at stake, such that reputation concerns can shape moralistic outrage and punishment even in one-shot anonymous interactions. We then support this account using data from Amazon Mechanical Turk. In anonymous experiments, subjects (total n = 8,440) report more outrage in response to others' selfishness when they cannot signal their trustworthiness through direct prosociality (sharing with a third party)-such that if the interaction were not anonymous, punishment would have greater signaling value. Furthermore, mediation analyses suggest that sharing opportunities reduce outrage by influencing reputation concerns. Additionally, anonymous experiments measuring costly punishment (total n = 6,076) show the same pattern: subjects punish more when sharing is not possible. Moreover, and importantly, moderation analyses provide some evidence that sharing opportunities do not merely reduce outrage and punishment by inducing empathy toward selfishness or hypocrisy aversion among non-sharers. Finally, we support the specific role of heuristics by investigating individual differences in deliberateness. Less deliberative individuals (who typically rely more on heuristics) are more sensitive to sharing opportunities in our anonymous punishment experiments, but, critically, not in punishment experiments where reputation is at stake (total n = 3,422); and not in our anonymous outrage experiments (where condemning is costless). Together, our results suggest that when nobody is watching, reputation cues nonetheless can shape outrage and-among individuals who rely on heuristics-costly punishment. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


The ablation of glial fibrillary acidic protein-positive cells from the adult central nervous system results in the loss of forebrain neural stem cells but not retinal stem cells.
The adult mammalian forebrain subependyma contains neural stem cells (NSCs) capable of self-renewal and multilineage differentiation. The in vivo identification of NSCs has not been definitively addressed using a loss of function approach. Using a transgenic mouse expressing herpes-simplex virus thymidine kinase from the glial fibrillary acidic protein (GFAP) promotor, we have selectively killed dividing GFAP-positive cells in the presence of ganciclovir (GCV) and shown a > 95% loss in the numbers of NSCs, as assayed by the formation of clonally derived neurospheres in vitro. This loss is seen following 3 days of GCV exposure in vivo or in vitro only and cannot be rescued by coculturing with pure astrocyte populations or control (green fluorescent protein-expressing) subependymal cells. Exposure to GCV in vitro has no effect on adult retinal stem cells hence, we conclude that adult forebrain NSCs comprise a subpopulation of the GFAP-positive cells within the subependyma.


Predicting stage 2 of calving in Holstein-Friesian heifers.
The objective of this study was to predict stage 2 of calving in Holstein-Friesian heifers. Interobserver reliability and predictive values of relevant signs of imminent parturition (i.e., tail raising, stepping, clear and bloody vaginal discharge, turning the head toward the abdomen, and lying lateral with abdominal contractions) were determined. In the first experiment 32 heifers were included. Three investigators participated as observers in the study. They walked through the precalving pen in pairs and observed pregnant heifers (≥267 d pregnant). Cohen's kappa results for the interobserver reliability were between 0.51 and 0.91. Thirty-seven Holstein-Friesian heifers were enrolled in the second experiment. Heifers were observed hourly for 24 h/d. Signs of imminent parturition that occurred were noted on a checklist. Compared with a precalving control period (4 d before calving), tail raising, clear vaginal discharge, and bloody vaginal discharge were more likely to occur during the last 24 h before calving. Two equations were built using the GENLINMIXED procedure to predict the hours until parturition. In version 1, the absence or presence of each sign of imminent parturition except turning the head toward the abdomen was included. In version 2, hours until parturition were estimated with the factors days of gestation, tail raising, and clear vaginal discharge. Relaxation of the broad pelvic ligaments and teat filling were evaluated twice per day. Prediction of calving with these parameters was not satisfying (positive predictive values were between 35.1 and 72.7% depending on the day of gestation). The possibility of excluding calving for the next 12 h was considerably higher, ranging from 88.5 to 97.1%. These results indicate that predicting stage 2 of calving via direct observation of plausible signs is imprecise and therefore not recommendable.


Mitochondrial targeting of human DNA glycosylases for repair of oxidative DNA damage.
Oxidative damage to mitochondrial DNA has been implicated in human degenerative diseases and aging. Although removal of oxidative lesions from mitochondrial DNA occurs, the responsible DNA repair enzymes are poorly understood. By expressing the epitope-tagged proteins in COS-7 cells, we examined subcellular localizations of gene products of human DNA glycosylases: hOGG1, hMYH and hNTH1. A gene encoding for hOGG1 which excises 7,8-dihydro-8-oxoguanine (8-oxoG) from DNA generates four isoforms by alternative splicing (types 1a, 1b, 1c and 2). Three tagged isoforms (types 1b, 1c and 2) were localized in the mitochondria. Type 1a protein, which exclusively contains a putative nuclear localization signal, was sorted to the nucleus and lesser amount to the mitochondria. hMYH, a human homolog gene product of Escherichia coli mutY was mainly transported into the mitochondria. hNTH1 protein excising several pyrimidine lesions was transported into both the nucleus and mitochondria. In contrast to the three DNA glycosylases, translocation of the human major AP endonuclease (hAPE) into the mitochondria was hardly observed in COS-7 cells. These results suggest that the previously observed removal of oxidative base lesions in mitochondrial DNA is initiated by the above DNA glycosylases.


Reading baby books: medicine, marketing, money and the lives of American infants.
This article examines American baby books from the late nineteenth through the twentieth century. Baby books are ephemeral publications—formatted with one or more printed pages for recording developmental, health, and social information about infants and often including personal observations, artifacts such as photographs or palm prints, medical and other prescriptive advice, and advertisements. For historians they serve as records of the changing social and cultural worlds of infancy, offering insights into the interplay of childrearing practices and larger social movements.Baby books are a significant historical source both challenging and supporting current historiography, and they illustrate how medical, market and cultural forces shaped the ways babies were cared for and in turn how their won behavior shaped family lives. A typology of baby books includes the lavishly illustrated keepsake books of the late nineteenth century, commercial and public health books of the twentieth century, and on-line records of the present day. Themes that emerge over time include those of scientific medicine and infant psychology, religion and consumerism. The article relies on secondary literature and on archival sources including the collections of the UCLA Louise M. Darling Biomedical Library as well as privately held baby books.


Effect of ageing on cervical or vaginal cancer in Swedish women previously treated for cervical intraepithelial neoplasia grade 3: population based cohort study of long term incidence and mortality.
To determine factors influencing long term risks for acquiring or dying from invasive cervical or vaginal cancer in women previously treated for cervical intraepithelial neoplasia grade 3 (CIN3). Population based cohort study conducted in 1958-2008, followed up until 2009 in the Swedish Cancer Registry and Swedish Cause of Death Register, linked to the Swedish Population Register. Standardised incidence and mortality ratios were calculated for the risk of acquiring or dying from vaginal or cervical cancer, with the general female population in Sweden as reference. Relative risks in multivariable regression models were also calculated, adjusting for follow-up duration, treatment period, and age at CIN3 treatment or attained age. Entire female population of Sweden. 150,883 women in Sweden diagnosed and treated with CIN3 and followed up for invasive cervical or vaginal cancer, and related mortality. The cohort comprised 3,148,222 woman years. Standardised incidence and mortality ratios, stratified by period for treatment. Relative standardised incidence ratios and standardised mortality ratios for age at acquiring or dying from cervical or vaginal cancer (attained age), adjusted for preset variables. Women previously diagnosed with CIN3 had an increased risk of dying from invasive cervical or vaginal cancer, compared with the general female population (standardised mortality ratio 2.35, 95% confidence interval 2.11 to 2.61). After age 60 years, these women had an accelerated increased risk of acquiring invasive cancer; a similar steep increase in mortality risk was seen after age 70. Regression analyses indicated that the increase in risk over time is highly attributable to ageing. Women previously treated for CIN3 are at increased risk of developing and dying from cervical or vaginal cancer, compared with the general female population. The risk accelerates above age 60 years, suggesting a need for lifelong surveillance of these women.


Mechanisms of alcoholic pancreatitis. Proceedings of a conference. Chicago, Illinois, USA, November 2002.
Long-term, heavy alcohol consumption is associated with both acute and chronic pancreatitis. Progression of pancreatitis may lead to multiple comorbidities including maldigestion, diabetes, and pancreatic cancer. Understanding the underlying molecular, biochemical, and cellular mechanisms by which alcohol ingestion leads to the development of pancreatitis may help to develop strategies for the treatment and prevention of the disease. The National Institute on Alcohol Abuse and Alcoholism and the Office of Rare Diseases of National Institutes of Health sponsored a satellite symposium on "Mechanisms of Alcoholic Pancreatitis" at the annual meeting of the American Pancreatic Association, Chicago, IL, November 2002. For this symposium, 8 speakers were invited to address the following issues: (1) epidemiology of alcoholic pancreatitis; (2) pathophysiology of alcoholic pancreatitis; (3) animal models of alcoholic pancreatitis--roles of cholecystokinin (CCK) and viral infections; (4) alcohol and zymogen activation in the pancreatic acinar cell; (5) role of alcohol metabolism in alcoholic pancreatitis; (6) pancreatic stellate cell activation in alcoholic pancreatitis; and (7) genetic predisposition to alcoholic chronic pancreatitis. It was concluded that alcohol abuse is a major contributory factor to the development of both acute and chronic pancreatitis. The injurious effects of ethanol on the pancreas may be mediated through (1) sensitization of acinar cells to CCK-induced premature activation of zymogens; (2) potentiation of the effect of CCK on the activation of transcription factors, nuclear factor kappaB (NF-kappaB) and activating protein-1 (AP-1); (3) generation of toxic metabolites such as acetaldehyde and fatty acid ethyl esters; (4) sensitization of the pancreas to the toxic effects of coxsackievirus B3; and (5) activation of pancreatic stellate cells by acetaldehyde and oxidative stress and subsequent increased production of collagen and other matrix proteins.


Polygenic score × intervention moderation: an application of discrete-time survival analysis to modeling the timing of first tobacco use among urban youth.
The present study examines the interaction between a polygenic score and an elementary school-based universal preventive intervention trial. The polygenic score reflects the contribution of multiple genes and has been shown in prior research to be predictive of smoking cessation and tobacco use (Uhl et al., 2014). Using data from a longitudinal preventive intervention study, we examined age of first tobacco use from sixth grade to age 18. Genetic data were collected during emerging adulthood and were genotyped using the Affymetrix 6.0 microarray. The polygenic score was computed using these data. Discrete-time survival analysis was employed to test for intervention main and interaction effects with the polygenic score. We found a main effect of the intervention, with the intervention participants reporting their first cigarette smoked at an age significantly later than controls. We also found an Intervention × Polygenic Score interaction, with participants at the higher end of the polygenic score benefitting the most from the intervention in terms of delayed age of first use. These results are consistent with Belsky and colleagues' (e.g., Belsky, Bakermans-Kranenburg, & van IJzendoorn, 2007; Belsky & Pleuss, 2009, 2013; Ellis, Boyce, Belsky, Bakermans-Kranenburg, & van IJzendoorn, 2011) differential susceptibility hypothesis and the concept of "for better or worse," wherein the expression of genetic variants are optimally realized in the context of an enriched environment, such as provided by a preventive intervention.


'Something so hard': a mixed-methods study of home sputum collection for tuberculosis contact investigation in Uganda.
Home sputum collection could facilitate prompt evaluation and diagnosis of tuberculosis (TB) among contacts of patients with active TB. We analyzed barriers to home-based collection as part of an enhanced intervention for household TB contact investigation in Kampala, Uganda. We conducted a convergent mixed-methods study to describe the outcomes of home sputum collection in 91 contacts and examine their context through 19 nested contact interviews and two focus group discussions with lay health workers (LHWs). LHWs collected sputum from 35 (39%) contacts. Contacts reporting cough were more likely to provide sputum than those with other symptoms or risk factors (53% vs. 15%, RR 3.6, 95%CI 1.5-2.8, P < 0.001). Males were more likely than females to provide sputum (54% vs. 32%, RR 1.7, 95%CI 1.0-2.8, P = 0.05). Contacts said support from the index patient and the convenience of the home visit facilitated collection. Missing containers and difficulty producing sputum spontaneously impeded collection. Women identified stigma as a barrier. LHWs emphasized difficulty in procuring sputum and discomfort pressing contacts to produce sputum. Home sputum collection by LHWs entails different challenges from sputum collection in clinical settings. More research is needed to develop interventions to mitigate stigma and increase success of home-based collection.


The use of local 17beta-oestradiol treatment for improving vaginal symptoms associated with post-menopausal oestrogen deficiency.
The effects of local 17beta-oestradiol therapy on the vaginal mucosa and endometrial thickness were studied in 35 post-menopausal women with symptoms of vaginal atrophy. Signs and symptoms of vaginal atrophy were measured by anamnesis, visual examination and the maturation index before and after 12 weeks' treatment with 17beta-oestradiol in the form of vaginal tablets. The maturation proportion on vaginal smear, endometrial thickness on transvaginal ultrasonography and plasma concentrations of follicle-stimulating hormone, luteinizing hormone and oestradiol were also determined. All vaginal atrophy signs and symptoms significantly improved and there was a significant increase in vaginal smear maturation with 17beta-oestradiol treatment. Endometrial thickness did not change significantly. It is concluded that 17beta-oestradiol improves the signs and symptoms of vaginal atrophy without causing endometrial stimulation and offers a safe and effective alternative to systemic hormone replacement therapy for the treatment of vaginal symptoms associated with post-menopausal oestrogen deficiency.