CERKL is upregulated in cutaneous squamous cell carcinoma and maintains cellular sphingolipids and resistance to oxidative stress.

BACKGROUND: Ceramide kinase-like protein (CERKL) was originally described in retinal tissue. CERKL has been shown to protect cells from oxidative stress, and mutations in CERKL underlie the inherited disease retinitis pigmentosa. CERKL expression maintains cellular sphingolipids via an unknown mechanism. OBJECTIVES: To determine whether CERKL is expressed in epidermis and cutaneous squamous cell carcinoma (cSCC) and whether CERKL expression affects cSCC sphingolipid metabolism and susceptibility to oxidative stress. METHODS: CERKL expression was determined by RNA-Seq, quantitative polymerase chain reaction and immunohistochemistry. CERKL was knocked down in cSCC cells using small interfering RNA. Sphingolipid content was analysed by liquid chromatography-mass spectrometry. Oxidative stress was induced by treatment with H2 O2 , and apoptosis was measured using flow cytometry to determine annexin V binding. RESULTS: CERKL mRNA and protein are highly expressed in actinic keratosis and cSCC in comparison with normal epidermis. CERKL is also expressed in metabolically active epithelial cells in normal hair bulbs and sebaceous glands. CERKL knockdown in cultured cSCC cells reduces cellular sphingolipid content and enhances susceptibility to oxidative stress. CONCLUSIONS: These findings suggest that CERKL may be important in cSCC progression and could lead to novel strategies for prevention and treatment of cSCC.

CERKL is Upregulated in Cutaneous Squamous Cell Carcinoma and Maintains Cellular Sphingolipids and Resistance to Oxidative Stress.

BACKGROUND: Ceramide Kinase-Like Protein (CERKL) was originally described in retinal tissue. CERKL has been shown to protect cells from oxidative stress, and mutations in CERKL underlie the inherited disease, retinitis pigmentosa. CERKL expression maintains cellular sphingolipids via an unknown mechanism. OBJECTIVES: To determine whether CERKL is expressed in epidermis and cutaneous squamous cell carcinoma (cSCC) and whether CERKL expression affects cSCC sphingolipid metabolism and susceptibility to oxidative stress. METHODS: CERKL expression was determined by RNA-Seq, qPCR and immunohistochemistry. CERKL was knocked down in cSCC cells using siRNA. Sphingolipid content was analyzed by liquid chromatography-mass spectrometry (LC-MS). Oxidative stress was induced by treatment with H2 O2 , and apoptosis was measured using flow cytometry to determine annexin v binding. RESULTS: CERKL mRNA and protein are highly expressed in actinic keratosis and cSCC in comparison with normal epidermis. CERKL also is expressed in metabolically active epithelial cells in normal hair bulbs and sebaceous glands. CERKL knockdown in cultured cSCC cells reduces cellular sphingolipid content and enhances susceptibility to oxidative stress. CONCLUSIONS: These findings suggest that CERKL may be important in cSCC progression and could lead to novel strategies for prevention and treatment of cSCC.

[Physiological hydronephrosis in pregnancy: Occurrence and possible causes. An MRI study]. / L'hydronéphrose physiologique durant la grossesse : prévalences et causes possibles. Une étude basée sur l'IRM.

INTRODUCTION: The etiology of the uretero-hydronephrosis in pregnancy is just hypothesis: hormonal or mechanical hypothesis, only investigated by echographic studies. MRI permits to visualize the entirety of the urinary tract, which can be helpful to find out a mechanical cause. METHODOLOGY: We have analysed the MRI of 100 asymptomatic pregnant women. We have determined the number and locations of the uretero-hydronephroses and researched whether there is any relationship between the uretero-hydronephrosis and certain abdominal structures. We focused on the psoas muscle and measured its depth, width and calculated its surface by a reproducible method. RESULTS: The analysis revealed that the uretero-hydronephrosis was predominantly at the right side (63%) and in the majority of the cases limited to the kidney (42%) and/or the proximal third of the ureter (42%). We were able to rule out some proposed etiologies: a compression of the ureter between the uterus and the iliac or ovarian vessels; a protective effect of the left intestinal structures. A link was observed between the psoas muscle and the physiological uretero-hydronephrosis: the ipsilateral psoas muscle seemed smaller in pregnant women presenting a uretero-hydronephrosis. CONCLUSION: We have highlighted a link between a physiological uretero-hydronephrosis during pregnancy and a lesser developped psoas muscle. The hypothesis proposed is that a smaller psoas muscle would have a less protective effect of the ureter due to a lesser development. This study offers a practical conclusion: a left sided uretero-hydronephrosis during pregnancy and/or including the entirety of the ureter is more probably a pathological hydronephrosis. LEVEL OF EVIDENCE: 4.

Extramammary Paget's Disease : Case Report of a Penoscrotal Presentation.

We report the case of a 72 year old male with penoscrotal extramammary Paget's disease (EMPD). The patient presented with an eczematous lesion on the scrotum extending on to the base of the penis. Given the persistent and progressive nature of the lesion a biopsy was taken which revealed a malignant lesion suggestive of extramammary Paget's disease. After performing a CAT-scan of the lower abdomen and inguinal region, which was negative, a primary surgical approach with curative intentions was taken. One year after surgery the patient is doing well and shows no sign of local recurrence.

Stress indicators in minorities with multiple sclerosis.

Black Americans with multiple sclerosis (MS) experience higher levels of disease-related disability compared to White Americans (Marrie et al., 2006). Comorbidities such as depression and anxiety, which are underdiagnosed and undertreated in this population, negatively impact quality of life and treatment outcomes for people living with multiple sclerosis (plwMS) (D'Alisa et al., 2006; Marrie et al., 2009; Stepleman et al., 2014). Acts of discrimination toward Black Americans is associated with stress, which is a contributing factor for depression (Carter, 2017; Nadimpalli, 2015; Williams and Mohammed, 2009). This study compared the severity of multiple sclerosis symptoms amongst Black Americans and White Americans, and whether worsened MS symptoms in Black Americans are associated with increased experiences of discrimination. Data was analyzed from 143 plwMS in the Stress Indicators in Minorities with Multiple Sclerosis (SiMMS) study. Using the Mann-Whitney U test, significant differences were found on the NIH Emotional Distress - Anxiety measure (U = 1466.500, p = 0.045) and NIH Sleep Disturbance measure (U = 1467.000, p = 0.044) between the Black participant and the White participant groups. Discrimination was significantly correlated with both NIH Emotional Distress - Anxiety (r = 0.677, p < .001) and NIH Sleep Disturbance (r = 0.446, p = .007) in Black MS individuals. Additionally, several physiological condition and psychological outcome measures were correlated with the NIH Emotional Distress - Anxiety and NIH Sleep Disturbance measures. This study contributes to literature highlighting the negative impacts of discrimination and race related stress on the physical and mental health of Black Americans.

Anderson localization in a periodic photonic lattice with a disordered boundary.

We investigate experimentally the light evolution inside a two-dimensional finite periodic array of weakly coupled optical waveguides with a disordered boundary. For a completely localized initial condition away from the surface, we find that the disordered boundary induces an asymptotic localization in the bulk, centered around the initial position of the input beam.

The effect of sertindole on QTD and TPTE.

OBJECTIVE: Recent research suggests that other surrogate markers than QTc, including QTc dispersion and Tpeak-Tend, may better correlate with cardiac arrhythmia risk. While sertindole significantly prolongs the QTc interval, the effects on other markers of arrhythmia risk, such as QTc dispersion and Tpeak-Tend are unknown. METHOD: Digital 12-lead ECG was recorded at baseline and at steady-state in 37 patients switched to sertindole. ECG was analysed for Fridericia-corrected QT duration (QTcF), QT dispersion and Tpeak-Tend. RESULTS: From a baseline QTcF of 407 +/- 22 ms, mean QTcF prolongation during sertindole treatment was 20 +/- 23 ms, P < 0.01. No effect on QTc dispersion was found (-1 +/- 11 ms; P = 0.41). No increased duration of the Tpeak-Tend interval from baseline was found (+7 +/- 21 ms; P = 0.05). CONCLUSION: These findings might be related to the absence of confirmed Torsade de Pointes (TdP) cases related to sertindole exposure, despite sertindole's QTc prolonging effects.

A comparison of the peri-operative data after open radical retropubic prostatectomy or robotic-assisted laparoscopic prostatectomy.

PURPOSES: To compare the peri-operative biochemical data, the postoperative need for help with hygiene and mobility, and the duration of bladder catheterization, hospitalization and ICU stay of patients undergoing radical retropubic prostatectomy (RRP) versus robotic-assisted laparoscopic prostatectomy (RALP) performed by an experienced open, yet inexperienced laparoscopic, surgical team, in a peripheral low-volume urological centre. METHODS: Over a 4-year period (2004-2008), 22 men underwent radical prostatectomy without lymphadenectomy at the study institution. The mean age of the patients was 63.9 years and the mean PSA value at the time of diagnosis was 9.2 ng/mL. RESULTS: Patients in the robotic-assisted laparoscopic prostatectomy group presented a significantly lower decrease in haemoglobin, haematocrit and total plasmatic protein and a significantly smaller need for help with hygiene and mobility and a shorter duration of bladder catheterization, hospitalization and ICU stay. CONCLUSIONS: The results of this study have shown that robotic-assisted laparoscopic prostatectomy is associated with lower peri-operative morbidity and a shorter hospital stay than radical retropubic prostatectomy, even when only considering the first performed robotic-assisted laparoscopic prostatectomies by a yet inexperienced robotic team in a peripheral low-volume urological centre.

The metabolic syndrome and schizophrenia.

OBJECTIVE: To summarize the accumulated data on metabolic syndrome prevalence in patients with schizophrenia, examine evidence for a biological contribution of the mental illness to metabolic risk and review novel options available for management of prediabetic states. METHOD: A Medline search using metabolic syndrome, insulin resistance and insulin sensitivity cross-referenced with schizophrenia was performed on articles published between 1990 and May 2008. RESULTS: Recent evidence indicates that schizophrenia increases predisposition towards metabolic dysfunction independent of environmental exposure. Both fasting and non-fasting triglycerides have emerged as important indicators of cardiometabolic risk, while metformin, thiazolidinediones and GLP-1 modulators may prove promising tools for managing insulin resistance. CONCLUSION: Because of lifestyle, disease and medication effects, schizophrenia patients have significant risk for cardiometabolic disease. Routine monitoring, preferential use of metabolically neutral antipsychotics and lifestyle education are critical to minimizing risk, with a possible role for antidiabetic medications for management of insulin resistant states that do not respond to other treatment strategies.

Which comes first: atypical antipsychotic treatment or cardiometabolic risk?

OBJECTIVE: To provide an overview for practicing clinicians on the pharmacological basis of cardiometabolic risk induced by antipsychotic drugs in patients with serious mental illness, to propose hypotheses to explain these risks and to give tips for managing cardiometabolic risk during antipsychotic treatment. METHOD: A MEDLINE search using terms for atypical antipsychotics (including individual drug names), metabolic, cardiovascular, weight gain and insulin resistance, cross-referenced with schizophrenia was performed on articles published between 1990 and May 2008. RESULTS: Strong evidence exists for significant cardiometabolic risk differences among several antipsychotic agents. Histamine H1 and serotonin 5HT2C antagonism are associated with risk of weight gain, but receptor targets for dyslipidemia and insulin resistance have not yet been identified. Convincing data indicate that hypertriglyceridemia and insulin resistance may occur in the absence of weight gain with certain antipsychotics. CONCLUSION: Although lifestyle and genetics may contribute independent risks of cardiometabolic dysfunction in schizophrenia and other serious mental illness, antipsychotic treatment also represents an important contributor to risk of cardiometabolic dysfunction, particularly for certain drugs and for vulnerable patients. Mental health professionals must learn to recognize the clinical signposts indicating antipsychotic-related cardiometabolic problems to forestall progression to type II diabetes, cardiovascular events and premature death.

Correlation between bone lesion changes and cartilage volume loss in patients with osteoarthritis of the knee as assessed by quantitative magnetic resonance imaging over a 24-month period.

OBJECTIVE: To evaluate in patients with knee osteoarthritis (OA) the size changes in bone oedema and cysts over 24 months, and to contrast these changes with cartilage volume loss using quantitative magnetic resonance imaging. METHODS: 107 patients with knee OA, selected from a large trial evaluating the effect of a bisphosphonate, were analysed by magnetic resonance imaging at baseline and 24 months. Assessments of subchondral bone oedema and cysts, and cartilage volume were done. RESULTS: At baseline, 86 patients showed the presence of at least one type of bone lesion: 71 oedema, 61 cysts and 51 both. At 24 months, although not statistically significant, the oedema total size change increased by 2.09 (SD 15.03) mm, and the cyst by 1.09 (8.13) mm; mean size change for the oedema was +0.38 (2.18) mm and -0.10 (4.36) mm for the cyst. When analysed according to subregions, an increase was found for the cyst size in the trochlea (+0.67 (2.74) mm, p = 0.02) and in the lateral tibial plateau (+0.15 (0.83) mm, p = 0.09), and for the oedema size in the medial tibial plateau (+1.73 (8.11) mm, p = 0.05). At 24 months, significant correlations were seen between the loss of cartilage volume and oedema size change in the medial condyle (-0.40, p = 0.0001) and the medial tibial plateau (-0.23, p = 0.03), and the changes in cyst size in the medial condyle (-0.29, p = 0.01). A multivariate analysis showed that the oedema size change was strongly and independently associated with medial cartilage volume loss (-0.31, p = 0.0004). CONCLUSION: These data demonstrate that bone lesions are prevalent in knee OA. The correlation of the oedema and cyst size increase in the medial compartment over time with a greater loss of cartilage volume in this area underlines the importance of subchondral bone lesions in OA pathophysiology.

Accuracy of body image perception and preferred weight loss strategies in schizophrenia: a controlled pilot study.

OBJECTIVE: Obesity in severely mentally ill (SMI) populations is an increasing problem, but there is no controlled data regarding the relationship between SMI and weight perception. METHOD: Fifty patients with schizophrenia and 50 demographically matched control participants were recruited. Weight, height, and body image accuracy were assessed for all participants, and assessments of mood, psychotic symptom severity and anxiety, and preferred modes of weight loss were assessed for the schizophrenia sample. RESULTS: Patients with schizophrenia were significantly more likely to be obese than controls (46% vs. 18%, P < 0.005), and most patients expressed an interest in losing weight. Obese participants with schizophrenia underestimated their body size (11.0%) more than controls (4.9%) (P < 0.05). CONCLUSION: Patients with schizophrenia are more likely to underestimate their body size, independent of the effects of obesity. However, they also express concern about weight issues and willingness to participate in psychoeducational groups targeted at weight loss.

UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia.

Nilotinib is a novel BCR-ABL inhibitor with significantly improved potency and selectivity over imatinib. In Phase I and Phase II clinical studies of nilotinib in patients with a variety of leukemias, infrequent instances of reversible, benign elevation of bilirubin were observed. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) glucuronidates bilirubin in humans, and a polymorphism in the promoter of the gene that encodes it has been associated with hyperbilirubinemia during treatment with a number of drugs. Pharmacogenetic analysis of that TA-repeat polymorphism found an association between the (TA)7/(TA)7 genotype and risk of hyperbilirubinemia in Phase I patients with imatinib-resistant/intolerant chronic myeloid leukemia (CML) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL); this result was replicated in two separate analyses of the chronic phase (CP) and accelerated phase (AP) CML arms of a Phase II study. As nilotinib is not known to be glucuronidated by UGT1A1, the combined impact of inhibition of UGT1A1 activity by nilotinib and genetic polymorphism is the most likely cause of the increased rate of hyperbilirubinemia.

Interactions between municipal solid waste incinerator bottom ash and bacteria (Pseudomonas aeruginosa).

Municipal solid waste incinerator bottom ash (MSWI BA) can be used in road construction where it can become exposed to microbial attack, as it can be used as a source of oligoelements by bacteria. The extent of microbial colonization of the bottom ash and the intensity of microbial processes can impact the rate of leaching of potentially toxic elements. As a consequence, our objective was to highlight the mutual interactions between MSWI bottom ash and Pseudomonas aeruginosa, a common bacteria found in the environment. Experiments were carried out for 133 days at 25 degrees C using a modified soxhlet's device and a culture medium, in a closed, unstirred system with weekly renewal of the aqueous phase. The solid products of the experiments were studied using a laser confocal microscopy, which showed that biofilms formed on mineral surfaces, possibly protecting them from leaching. Our results show that the total mass loss after 133 days is systematically higher in abiotic medium than in the biotic one in proportions going from 31 to 53% depending on element. Ca and Sr show that rates in biotic medium was approximately 19% slower than in abiotic medium during the first few weeks. However, in the longer term, both rates decreased to reach similar end values after 15 weeks. By taking into account the quantities of each tracer trapped in the layers we calculate an absolute alteration rate of MSWI BA in the biotic medium (531 microg m(-2) d(-1)) and in the abiotic one (756 microg m(-2) d(-1)).

Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency.

To evaluate the role of tumor necrosis factor (TNF alpha) in bone loss resulting from estrogen deficiency, the effects of ovariectomy were explored in six-month-old transgenic mice expressing high blood levels of a soluble TNF receptor type I (sTNFR1)-FcIgG3 fusion protein, which neutralizes TNF alpha, and in their nontransgenic littermates used as controls. These transgenic mice were identical to control mice in bone mass (evaluated by bone mineral density and content) and strength. 12 weeks after ovariectomy, the decrease in bone mass and increase in osteocalcin (marker of bone turnover) found in control mice were not observed in transgenic mice, which were not different from sham-operated mice, transgenic or not. This observation suggests a critical role for TNF alpha in the pathogenesis of bone loss induced by estrogen deficiency, a common cause of morbidity in postmenopausal women.

Microbially-mediated glass dissolution and sorption of metals by Pseudomonas aeruginosa cells and biofilm.

A basaltic glass and a vitrified bottom ash were incubated at 25 degrees C in a growth medium (based on casaminoacids) inoculated with Pseudomonas aeruginosa. Bacterial growth and mineral concentrations in different compartments (bacterial cells, growth medium and biofilm) were monitored in short-term (3 days), and long-term experiments involving repeated renewals of the culture medium during 174 days. In short-term experiments, while the concentration of iron increased in the presence of bacteria, a decrease in Ni and Zn was observed in the growth medium compared to the sterile condition. During long-term experiments, such differences gradually decreased and disappeared after 78 days. On the contrary, iron concentration remained higher in the biotic condition compared to the sterile one. Bacterial growth resulted within a few days in the formation of a biofilm, which lead to the cementation of the altered glass grains. Most of the constituents of the glass (Si, Mg, Fe, Ti, Ba, Co, Zn, Cu, Ni and Cr) were found in the biofilm, while the chemical composition of the bacterial cells was very different.

The Virginia Twin Study of Adolescent Behavioral Development. Influences of age, sex, and impairment on rates of disorder.

BACKGROUND: The Virginia Twin Study of Adolescent Behavioral Development is a cohort-longitudinal epidemiological study that uses the genetic twin design to study the development and maintenance of child psychiatric disorders. We determined the rates of DSM-III-R disorders, disorders with impairment, and age, sex, and comorbidity effects. METHODS: Families of 2762 white twins aged 8 to 16 years participated. Twins and their parents were asked systematically about risk factors and current psychiatric symptoms by means of investigator-based psychiatric interviews and questionnaires. The DSM-III-R diagnoses were made for major depressive disorder, separation anxiety, overanxious disorder, simple phobia, social phobia, agoraphobia, oppositional defiant disorder, conduct disorder, and attention deficit hyperactivity disorder. RESULTS: The 3-month point prevalence for any DSM-III-R disorders was 413 per 1000, and that for disorders with associated impairment was 142 per 1000. Emotional disorders with impairment occurred in 89 per 1000, with girls being more commonly affected; behavioral disorders had a prevalence of 71 per 1000, with boys being more frequently affected. The proportion with disorder who also had functional impairment varied across disorders; anxiety and phobic disorders were particularly likely not to be accompanied by impairment. Rates of emotional and behavioral disorders increased over the age range. There was extensive comorbidity among disorders. CONCLUSIONS: The prevalence rates and patterns of findings from this study of twins are consistent with those of other epidemiological studies, supporting previous findings of few differences in rates of psychiatric disorder between twins and singletons. The importance of including measures of functional impairment is evident by its effect on rates of disorder and patterns of comorbidity.

Co-occurrence of abuse of different drugs in men: the role of drug-specific and shared vulnerabilities.

BACKGROUND: Previous research has demonstrated genetic and environmental influences on abuse of individual substances, but there is less known about how these factors may influence the co-occurrence of abuse of different illicit drugs. METHODS: We studied 3372 male twin pairs from the Vietnam Era Twin Registry. They were interviewed using the Diagnostic Interview Schedule, Version III, Revised to investigate the extent to which the abuse of different categories of drugs occurs together within an individual, as well as the possibility that genetic and environmental factors are responsible for observed co-occurrence. Co-occurrence was quantified using odds ratios and conditional probabilities. Multivariate biometrical modeling analyses were used to assess genetic and environmental influences on co-occurrence. RESULTS: Abusing any category of drug was associated with a marked increase in the probability of abusing every other category of drugs. We found evidence for a shared or common vulnerability factor that underlies the abuse of marijuana, sedatives, stimulants, heroin or opiates, and psychedelics. This shared vulnerability is influenced by genetic, family environmental, and nonfamily environmental factors, but not every drug is influenced to the same extent by the shared vulnerability factor. Marijuana, more than other drugs, was influenced by family environmental factors. Each category of drug, except psychedelics, had genetic influences unique to itself (ie, not shared with other drug categories). Heroin had larger genetic influences unique to itself than did any other drug. CONCLUSION: There are genetically and environmentally determined characteristics that comprise a shared or common vulnerability to abuse a range of illicit drugs.

A registry-based twin study of depression in men.

BACKGROUND: The only large, registry-based twin study of depression using diagnostic criteria assessed by structured interview included only women. We present results from a comparable study of men. METHODS: Data were collected using a standardized telephone interview of men from the Vietnam Era Twin Registry. Both twins from 3372 pairs participated. Proband-wise concordance rates and biometric modeling were used to analyze the data. RESULTS: The diagnosis of major depression (MD), as defined by DSM-III-R, and the subtype of severe/psychotic MD were significantly affected by genetic (h2=0.36 and 0.39, respectively) and nonshared environmental (e2=0.64 and 0.61, respectively) factors but not by family environmental factors. Dysthymia and mild and moderate MD were affected by family environmental (c2=0.27, 0.08, and 0.14, respectively) and nonshared environmental (e2=0.73, 0.92, and 0.86, respectively) factors but not by genetic factors. Early-onset (before age 30 years) and late-onset (after age 30 years) MD were significantly affected by genetic (h2=0.47 and 0.10, respectively) and nonshared environmental (e2=0.53 and 0.90, respectively) factors. Early-onset MD was significantly more heritable than late-onset MD. CONCLUSIONS: The magnitude of genetic and environmental effects on depression in men is similar to that previously reported in women. Also similar to previous findings, more severe and earlier-onset depression may be more strongly affected by genetic factors, but differences in the reliability of reports of depression associated with severity may inflate estimates of the effect of the unique environment and deflate heritability estimates for less severe depression.