A Review of Radiation-Induced Vascular Injury and Clinical Impact.

ABSTRACT: The number of cancer survivors continues to increase because of advances in therapeutic modalities. Along with surgery and chemotherapy, radiotherapy is a commonly used treatment modality in roughly half of all cancer patients. It is particularly helpful in the oncologic treatment of patients with breast, head and neck, and prostate malignancies. Unfortunately, among patients receiving radiation therapy, long-term sequalae are often unavoidable, and there is accumulating clinical evidence suggesting significant radiation-related damage to the vascular endothelium. Ionizing radiation has been known to cause obliterative fibrosis and increased wall thickness in irradiated blood vessels. Clinically, these vascular changes induced by ionizing radiation can pose unique surgical challenges when operating in radiated fields. Here, we review the relevant literature on radiation-induced vascular damage focusing on mechanisms and signaling pathways involved and highlight microsurgical anastomotic outcomes after radiotherapy. In addition, we briefly comment on potential therapeutic strategies, which may have the ability to mitigate radiation injury to the vascular endothelium.

Understanding the Role of Adipocytes and Fibroblasts in Cancer.

ABSTRACT: Cancer is currently the second leading cause of death in the United States. There is increasing evidence that the tumor microenvironment (TME) is pivotal for tumorigenesis and metastasis. Recently, adipocytes and cancer-associated fibroblasts (CAFs) in the TME have been shown to play a major role in tumorigenesis of different cancers, specifically melanoma. Animal studies have shown that CAFs and adipocytes within the TME help tumors evade the immune system, for example, by releasing chemokines to blunt the effectiveness of the host defense. Although studies have identified that adipocytes and CAFs play a role in tumorigenesis, adipocyte transition to fibroblast within the TME is fairly unknown. This review intends to elucidate the potential that adipocytes may have to transition to fibroblasts and, as part of the TME, a critical role that CAFs may play in affecting the growth and invasion of tumor cells. Future studies that illuminate the function of adipocytes and CAFs in the TME may pave way for new antitumor therapies.

Enuresis and encopresis: Association with child abuse and neglect.

OBJECTIVE: Several reports suggest a possible link between child abuse and enuresis or encopresis but concern small series of children and present therefore methodological biases. The objective of the present study was to clarify this issue by examining the relationships between child abuse and enuresis or encopresis in a large sample of children. METHODS: A multicenter cross-sectional study was conducted on a sample of 428 children in social residential centers in France. Four types of child abuse were considered: sexual abuse, physical abuse, psychological abuse and neglect. The accuracy and reliability of the characterization of the type of abuse as well as that of the sphincter disorder was particularly high. In fact, all the cases benefited from both a social and a psychological investigation and from an observation in a residential center. RESULTS: More than 60% of the children were victims of at least one type of abuse. Encopresis was reported in 15 children (3.5% [95% CI: 2.0%-5.7%]), mostly among boys (13 cases). Enuresis affected 54 of the 390 children aged five years or more (13.8% [95% CI: 10.6%-17.7%]). Most of the cases also appeared in boys (38 cases). Rates of encopresis were found to be seven-fold higher in both psychologically abused and neglect children compared to non-abused children (P=0.01). Concerning enuresis, a weaker but still significant association was found with sexual (OR= 3.3, P=0.025) and physical abuse (OR=2.3, P=0.035). CONCLUSION: Our findings support the hypothesis that enuresis and encopresis are associated with specific types of child abuse.

Self-representation in Kleine-Levin syndrome: a single case fMRI study.

Kleine-Levin syndrome (KLS) is characterized by recurrent episodes of hypersomnia, compulsive hyperphagia, disinhibition, hypersexuality and self modifications. To investigate the Self, we used afunctional magnetic resonance imaging paradigm evaluating Self-reference processing (SRP) and Self-reference effect (SRE) in a17-year-old male adolescent at the end of an episode. We observed enhanced activations in right hemisphere and posterior areas- associated with physical Self representations- during the SRP condition, while during the SRE condition, enhanced activations in bilateral but prevailing left frontal areas- associated with the conceptual Self. These results suggest amodified Self during aKLS episode being more physically grounded.

Dietary guanidinoacetate reduces spaghetti meat myopathy risk in the breast muscle of broiler chickens.

The global demand for white chicken meat along with the increase in the occurrence of growth-related breast muscle myopathies (BMMs) [namely white striping (WS), wooden breast (WB), and spaghetti meat (SM)] highlights the need for solutions that will improve meat quality while maintaining the high productivity of modern broilers. Guanidinoacetate (GAA), a precursor of creatine, is used as a feed additive and has previously shown the potential to affect the quality of breast meat. This study investigated growth performance, meat quality and the risk ratio for the development of BMMs in broilers assigned to two dietary treatments: control (CON) group, fed a commercial basal diet, and supplemented GAA (sGAA) group, receiving the control diet supplemented on top with 0.06% GAA. Growth performance indicators such as BW, daily weight gain, daily feed intake, feed conversion ratio and cumulative feed conversion ratio were recorded on a pen basis. As a trait affecting animal welfare, the occurrence of foot pad dermatitis was also evaluated. At day 43, birds were processed, and breasts were scored for the incidence and severity of BMMs (n = 166 and 165 in CON and sGAA groups, respectively). Quality traits (ultimate pH, colour) and technological properties (i.e., drip and cooking losses, marinade uptake, shear force, and oxidation levels of the lipid and the protein fractions) of breast meat were assessed in both treatments on samples not showing any macroscopic sign of BMMs (n = 20 breast fillets per group). Data of myopathy risk ratio were analysed as the risk for each group to develop WS, WB, and SM myopathies. Our results show that while sGAA and control groups did not differ significantly in growth performance, a remarkably beneficial effect of GAA was observed on the incidence of BMMs with significantly reduced risk of sGAA group to develop SM myopathy. The risk of sGAA group to develop SM was 30% lower compared to CON (P = 0.028). Finally, a significantly lower drip loss was observed in sGAA in comparison with CON (1.78 vs 2.48%, P = 0.020). Together, our results show that the inclusion of 0.06% GAA in feed can improve the water-holding capacity of meat and reduce the risk to develop SM myopathy without compromising the performance of broilers.

Assessment of Need for Improved Identification of a Culprit Drug in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

Importance: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe hypersensitivity reaction. Identifying a culprit drug is critical for patient care, yet identification is based on clinical judgment. Data are limited on the accuracy in or approach to identifying a culprit drug. Objective: To evaluate patient allergy list outcomes, current approaches in identifying culprit drugs, and potential methods of improving culprit drug identification. Design, Setting, and Participants: This retrospective cohort study spanned 18 years (January 2000 to July 2018), was conducted at Brigham and Women's Hospital and Massachusetts General Hospital (Boston), and included patients with clinically and histologically confirmed cases of SJS/TEN overlap and TEN. Main Outcomes and Measures: This study descriptively analyzed potential culprits to SJS/TEN, patients' allergy lists, and currently used approaches that led to those lists. It then tested the theoretical contribution of incorporating various parameters to allergy list outcomes. Results: Of 48 patients (29 women [60.4%]; 4 Asian [8.3%], 6 Black [12.5%], 5 Hispanic [10.4%], and 25 White [52.1%] individuals; median age, 40 years [range, 1-82 years]), the mean (SD) number of drugs taken per patient at disease onset was 6.5 (4.7). Physicians labeled 17 patients as allergic to a single culprit drug. Comparatively, 104 drugs were added to allergy lists across all patients. Physicians' approaches relied largely on heuristic identification of high-notoriety drugs and the timing of drug exposure. Use of a vetted database for drug risk improved sensitivity. Algorithm for Drug Causality for Epidermal Necrolysis scoring was discordant in 28 cases, labeling an additional 9 drugs missed by physicians and clearing 43 drugs labeled as allergens by physicians. Human leukocyte antigen testing could have potentially affected 20 cases. Consideration of infection as a culprit was limited. Conclusions and Relevance: The results of this cohort study suggest that currently used approaches to identify culprit drugs in SJS/TEN are associated with overlabeling patients allergic to likely nonculprit drugs and less commonly missed possible culprit drugs. Incorporation of a systematized unbiased approach could potentially improve culprit drug identification, although ultimately a diagnostic test is necessary.

Muscle and neuronal guidepost-like cells facilitate planarian visual system regeneration.

Neuronal circuits damaged or lost after injury can be regenerated in some adult organisms, but the mechanisms enabling this process are largely unknown. We used the planarian Schmidtea mediterranea to study visual system regeneration after injury. We identify a rare population of muscle cells tightly associated with photoreceptor axons at stereotyped positions in both uninjured and regenerating animals. Together with a neuronal population, these cells promote de novo assembly of the visual system in diverse injury and eye transplantation contexts. These muscle guidepost-like cells are specified independently of eyes, and their position is defined by an extrinsic array of positional information cues. These findings provide a mechanism, involving adult formation of guidepost-like cells typically observed in embryos, for axon pattern restoration in regeneration.

Nuclear receptor NR4A is required for patterning at the ends of the planarian anterior-posterior axis.

Positional information is fundamental to animal regeneration and tissue turnover. In planarians, muscle cells express signaling molecules to promote positional identity. At the ends of the anterior-posterior (AP) axis, positional identity is determined by anterior and posterior poles, which are putative organizers. We identified a gene, nr4A, that is required for anterior- and posterior-pole localization to axis extremes. nr4A encodes a nuclear receptor expressed predominantly in planarian muscle, including strongly at AP-axis ends and the poles. nr4A RNAi causes patterning gene expression domains to retract from head and tail tips, and ectopic anterior and posterior anatomy (e.g., eyes) to iteratively appear more internally. Our study reveals a novel patterning phenotype, in which pattern-organizing cells (poles) shift from their normal locations (axis extremes), triggering abnormal tissue pattern that fails to reach equilibrium. We propose that nr4A promotes pattern at planarian AP axis ends through restriction of patterning gene expression domains.

Perinatal grief following neonatal comfort care for lethal fetal condition.

BACKGROUND: The objective of the study was to assess perinatal grief experienced after continuing pregnancy and comfort care in women diagnosed with lethal fetal condition compared with termination of pregnancy for fetal anomaly (TOPFA). METHODS: This was a retrospective observational study which included women who chose to continue their pregnancy after the diagnosis of lethal fetal condition with comfort care support at birth at the Prenatal Diagnosis Center of Rennes Hospital from January 2007 to January 2017. Women were matched with controls who underwent TOPFA for the same type of fetal anomaly, gestational age at diagnosis and year. Women were evaluated by a questionnaire including the Perinatal Grief Scale. RESULTS: There were 28 patients in the continuing pregnancy group matched with 56 patients in the TOPFA group. Interval between fetal loss and completion of questionnaire was 6±3 years. Perinatal grief score was similar at 61±22 vs 58±18 (p = 0.729) in the continuing pregnancy and TOPFA groups, respectively. Women in the TOPFA group expressed more guilt. The cesarean-section rate in the continuing pregnancy group was 25%. CONCLUSION: Perinatal grief experienced by women opting for continuing pregnancy and comfort care after diagnosis of a potentially lethal fetal anomaly is not more severe than for those choosing TOPFA.

[Clinical approach and epidemiological aspects of mood and anxiety disorders during pregnancy and postpartum. Review and synthesis]. / Clinique et épidémiologie des troubles anxieux et dépressifs de la grossesse et du post-partum. Revue et synthèse.

The aim of this article is to review clinical and epidemiological data on pre- and postnatal anxious and depressive disorders. To this end, we systematically analysed definitions, prevalence, risk factors and obstetrical consequences of perinatal disorders, as reported in seminal as well as more recent publications. We report and discuss the most consensual results about anxious and depressive disorders of pregnancy and the postpartum, with special emphasis on maternity blues, postpartum depression and postpartum psychosis. Reviewed data confirm that the perinatal period is a time of high risk for the onset or exacerbation of several anxious or depressive disorders, which are likely to impede the normal progress of pregnancy or the child's development. The potential severity of bipolar disorders and puerperal psychosis is highlighted by the fact that they heavily contribute to maternal mortality. The specificity of perinatal disorders, their impact on public health, the extensive research and mounting knowledge in that field, provide ample justification for the recognition of perinatal psychiatry as a distinct branch of psychiatry.

[Psychological and pharmacological treatments of mood and anxiety disorders during pregnancy and postpartum. Review and synthesis]. / Thérapeutique des troubles anxieux et dépressifs de la grossesse et du post-partum. Revue et synthèse.

The aim of this article is to review the main methods of treatment of anxious and depressive disorders during pregnancy and the postpartum. To this end, we analyse recent publications about the use and efficacy of psychotherapy and psychosocial interventions (cognitive behavioural therapy, interpersonal psychotherapy, psychoanalytical therapy) in the perinatal period. We also review recent papers about the use of psychotropic medication during pregnancy and breast-feeding, with special emphasis on clinical trials. We particularly focus on the risk/benefit assessment of antidepressants, mood stabilisers, antipsychotics and benzodiazepines, in terms of teratogenicity, and impact on neonatal adaptation and neuropsychological development. Various treatment modalities are presented and discussed. It appears that psychotherapies have proved their efficiency on most pre- and postpartum anxious and depressive disorders and represent a first line treatment in most cases. Psychopharmacological treatment is indicated for severe anxious and depressive disorders. The risks of such medication, especially antidepressants, may have been overestimated in the past. Provided reasonable precautions are taken and mothers and future mothers receive clear information on the potential risks and benefits, psychotropic medication could be more broadly prescribed during pregnancy and the breast-feeding period.

Landmarks in Existing Tissue at Wounds Are Utilized to Generate Pattern in Regenerating Tissue.

Regeneration in many organisms involves the formation of a blastema, which differentiates and organizes into the appropriate missing tissues. How blastema pattern is generated and integrated with pre-existing tissues is a central question in the field of regeneration. Planarians are free-living flatworms capable of rapidly regenerating from small body fragments [1]. A cell cluster at the anterior tip of planarian head blastemas (the anterior pole) is required for anterior-posterior (AP) and medial-lateral (ML) blastema patterning [2-4]. Transplantation of the head tip into tails induced host tissues to grow patterned head-like outgrowths containing a midline. Given the important patterning role of the anterior pole, understanding how it becomes localized during regeneration would help explain how wounds establish pattern in new tissue. Anterior pole progenitors were specified at the pre-existing midline of regenerating fragments, even when this location deviated from the ML median plane of the wound face. Anterior pole progenitors were specified broadly on the dorsal-ventral (DV) axis and subsequently formed a cluster at the DV boundary of the animal. We propose that three landmarks of pre-existing tissue at wounds set the location of anterior pole formation: a polarized AP axis, the pre-existing midline, and the dorsal-ventral median plane. Subsequently, blastema pattern is organized around the anterior pole. This process, utilizing positional information in existing tissue at unpredictably shaped wounds, can influence the patterning of new tissue in a manner that facilitates integration with pre-existing tissue in regeneration.

Study of the mutagenic activity of 6 hepatotoxic pharmaceutical drugs in the Salmonella typhimurium microsome test, and the HGPRT and Na+/K+ ATPase system in cultured mammalian cells.

Several pharmaceutical drugs show strong hepatotoxicity during therapeutic use. We have studied 6 of them: aminophenazone, clofibrate, nifuroxazide, oxamniquine, perhexiline maleate, tienilic acid. Their mutagenicity was assessed in the Ames test on 6 strains of Salmonella typhimurium, and in V79 Chinese hamster lung cells using a rat-hepatocyte-mediated metabolic activation system and the HGPRT and Na+/K+ ATPase assay. Nifuroxazide was positive in the Ames test in two Salmonella strains (TA100, and TA100 Fr1). In the hepatocyte-mediated mammalian V79 cell system, nifuroxazide, clofibrate and aminophenazone were negative; oxamniquine and tienilic acid were positive with and without metabolic activation in tests looking for ouabain and 6-thioguanine resistance. Perhexiline maleate was negative for the direct induction of 6-thioguanine resistance without metabolic activation, and positive after metabolisation mediated by primary rat's hepatocytes. These results suggest the need for some caution in the use of some pharmaceutical drugs because of hepatotoxicity and because 3 out of 6 drugs were shown to be slightly mutagenic in mammalian cells.

Mutagenic activity of 4 active-principle forms of pharmaceutical drugs. Comparative study in the Salmonella typhimurium microsome test, and the HGPRT and Na+/K+ ATPase systems in cultured mammalian cells.

The nitroimidazole derivatives used in human therapy have shown a strong mutagenic activity in bacterial tests using Ames strains of Salmonella typhimurium. Our study compared the response of 4 products of this family on bacterial target cells as well as on mammalian target cells (Chinese hamster V79 cells). The strong positive response on TA100 was greatly reduced on the nitroreductase-deficient strain TA100 Frl. Furthermore, no mutagenic activity was found in V79 mammalian cells that we examined for ouabain and 6-thioguanine resistance.

Application of the Salmonella typhimurium microsome test to the study of 25 drugs belonging to 5 chemical series.

25 active-principle forms of pharmaceutical drugs belonging to 5 chemical series have been tested for mutagenic activity. To screen these drugs we used the Salmonella typhimurium assay on 5-histidine-requiring strains, with and without microsomal activation. Only the 3 nitroimidazole derivatives were mutagenic for strains TA100, TA1535 and TA98.

Control of the cryosurgical process in nonideal materials.

A study of a controlled cryosurgical process is presented. This study is based on the energy equations describing the probe response and the phase change occurring in the medium. First-order nonlinear differential equations (state equations) are obtained by applying the integral-solution method. In order to obtain maximal cell destruction, it is desired to control a specific cooling rate at the solid-liquid interface. This cooling rate defines the desired trajectories of the state variables through the state equations. In order to satisfy the cooling rate condition on the freezing front, a closed-loop is designed to control the probe temperature program. A simple analysis of the system stability employed linearization at several points along the desired trajectories. Ranges of stability were obtained for a system containing a proportional-integral controller. It was demonstrated that these stability ranges depend mainly on the selected sampling time of the discrete control loop and that the phase-change process does not significantly affect the stability results. A complete study of the nonlinear equations was performed by a computer simulation program which enables the selection of the final values of the controller parameters, in order to minimize the error and to ensure stability. In addition, the simulation program gives information about the effects of the A/D and D/A converters accuracy on the performance of the control loop. An A/D converter accuracy of 12 bits was found necessary in order to reduce the oscillations in probe temperature to acceptable values. The simulation also yields a complete calculated temperature field in the tissue during the controlled process. From these simulated results it can be seen that oscillations of +/- 0.5 degrees C in the desired probe temperature do not significantly affect the desired cooling rate at the freezing front. An initial overshoot of 1.5 degrees C in the desired probe temperature was obtained both experimentally and theoretically from the simulation. When this initial overshoot occurs at the beginning of the freezing process, it causes an error in freezing front velocity and consequently in ice-front position. From the numerical simulation, it can be deduced that the cooling rate obtained at the front deviates from the desired value by approximately 1%. The probe-temperature error increases at two instants: a) during the super-cooling effect and the subsequent sudden crystallization, and b) when the probe temperature is below -80 degrees C and unstable boiling of the cooling medium causes oscillations.

A biomechanical model of index finger dynamics.

A dynamic model of the biomechanics of the index finger for flexion-extension and abduction-adduction motion is introduced. The model takes into account all the tendons in the finger and relates to their varying moment arms during motion. A new set of moment arm coefficients and elongation equations is derived based on experimental measurements of previous studies. Constraint equations using variable coefficients are introduced and an optimization approach used to obtain the tendon forces required for any given motion and external force. The model and optimization approach are tested with data from a rapid pinch experiment as well as a hypothetical disc rotation. Good correlation is obtained with respect to electromyographic data in the literature.