Photosensitizing antihypertensive drug use and risk of cutaneous squamous cell carcinoma.

BACKGROUND: Many antihypertensive drugs (ADs) are photosensitizing, heightening reactivity of the skin to sunlight. Photosensitizing ADs have been associated with lip cancer, but whether they impact the risk of cutaneous squamous cell carcinoma (cSCC) is unknown. OBJECTIVES: To examine the association between AD use and cSCC risk among a cohort of non-Hispanic white individuals with hypertension enrolled in a comprehensive integrated healthcare delivery system in northern California (n = 28 357). METHODS: Electronic pharmacy data were used to determine exposure to ADs, which were classified as photosensitizing, nonphotosensitizing or unknown, based on published literature. We identified patients who developed a cSCC during follow-up (n = 3010). We used Cox modelling to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Covariates included age, sex, smoking, comorbidities, history of cSCC and actinic keratosis, survey year, healthcare utilization, length of health plan membership and history of photosensitizing AD use. RESULTS: Compared with nonuse of ADs, risk of cSCC was increased with ever having used photosensitizing ADs (aHR = 1·17, 95% CI 1·07-1·28) and ever having used ADs of unknown photosensitizing potential (aHR = 1·11, 95% CI 1·02-1·20), whereas no association was seen with ever having used nonphotosensitizing ADs (aHR = 0·99; 95% CI 0·91-1·07). Additionally, there was a modest increased risk with an increased number of prescriptions for photosensitizing ADs (aHR = 1·12, 95% CI 1·02-1·24; aHR = 1·19, 95% CI 1·06-1·34; aHR = 1·41, 95% CI 1·20-1·67 for one to seven, eight to 15 and ≥ 16 fills, respectively). CONCLUSIONS: These findings provide moderate support for an increased cSCC risk among individuals treated with photosensitizing ADs.

Hydrochlorothiazide use is strongly associated with risk of lip cancer.

BACKGROUND: The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. OBJECTIVES: To study the association between use of hydrochlorothiazide and squamous cell carcinoma of the lip. METHODS: We conducted a case-control study using Danish nationwide registry data. From the Cancer Registry (2004-2012), we identified 633 case patients with squamous cell carcinoma (SCC) of the lip and matched them to 63 067 population controls using a risk-set sampling strategy. Hydrochlorothiazide use (1995-2012) was obtained from the Prescription Registry and defined according to cumulative use. Applying conditional logistic regression, we calculated odds ratios (ORs) for SCC lip cancer associated with hydrochlorothiazide use, adjusting for predefined potential confounders obtained from demographic, prescription and patient registries. RESULTS: Ever-use of hydrochlorothiazide was associated with an adjusted OR for SCC lip cancer of 2.1 (95% confidence interval (CI): 1.7-2.6), increasing to 3.9 (95%CI: 3.0-4.9) for high use (≥25 000 mg). There was a clear dose-response effect (P < 0.001), with the highest cumulative dose category of hydrochlorothiazide (≥100 000 mg) presenting an OR of 7.7 (95%CI: 5.7-10.5). No association with lip cancer was seen with use of other diuretics or nondiuretic antihypertensives. Assuming causality, we estimated that 11% of the SCC lip cancer cases could be attributed to hydrochlorothiazide use. CONCLUSIONS: Hydrochlorothiazide use is strongly associated with an increased risk of lip cancer.

Pilot study to evaluate a plasma device for the treatment of onychomycosis.

Onychomycosis is a fungal infection of the nail unit, and is the most common of the nail disorders. Current therapies for onychomycosis have less than ideal efficacy and have the potential for adverse effects. As previous studies have shown that nonthermal plasma inhibits the in vitro growth of Trichophyton rubrum, we conducted a pilot study on 19 participants with toenail onychomycosis. The primary endpoint was safety of the device, and secondary outcome measures were clinical efficacy and mycological cure. Patient satisfaction was measured using questionnaires at the completion of the study. All but one patient met the primary endpoint of safety and there were no long-term sequelae. The overall clinical cure was 53.8% and the mycological cure was 15.4%. The majority of patients were satisfied with the treatment. Our conclusions are that nonthermal plasma is a safe treatment and may have a beneficial effect on toenail onychomycosis.

γ134.5-deleted HSV-1-expressing human cytomegalovirus IRS1 gene kills human glioblastoma cells as efficiently as wild-type HSV-1 in normoxia or hypoxia.

Pathophysiological hypoxia, which fosters the glioma stem-like cell (GSC) phenotype, is present in high-grade gliomas and has been linked to tumor development, invasiveness and resistance to chemotherapy and radiation. Oncolytic virotherapy with engineered herpes simplex virus-1 (HSV-1) is a promising therapy for glioblastoma; however, the efficacy of γ(1)34.5-deleted HSVs, which have been used in clinical trials, was diminished in hypoxia. We investigated the ability of a chimeric human cytolomegalovirus (HCMV)/HSV-1 virus, which expresses the human CMV protein kinase R evasion gene IRS1 and is in preparation for clinical trials, to infect and kill adult and pediatric patient-derived glioblastoma xenografts in hypoxia and normoxia. Infectivity, cytotoxicity and viral recovery were significantly greater with the chimeric virus compared with the γ(1)34.5-deleted virus, regardless of oxygen tension. The chimeric virus infected and killed CD133+ GSCs similarly to wild-type HSV-1. Increased activation of mitogen-activated protein kinase p38 and its substrate heat-shock protein 27 (Hsp27) was seen after viral infection in normoxia compared with hypoxia. Hsp27 knockdown or p38 inhibition reduced virus recovery, indicating that the p38 pathway has a role in the reduced efficacy of the γ(1)34.5-deleted virus in hypoxia. Taken together, these findings demonstrate that chimeric HCMV/HSV-1 efficiently targets both CD133+ GSCs and glioma cells in hypoxia.

Comparison of low and high dose cosyntropin stimulation tests in the diagnosis of adrenal insufficiency in septic shock patients.

Stress situations such as septic shock are accompanied by activation of the HPA axis. Some patients do not activate this axis in stress situations. This blunted response is currently designated as critical illness-related corticosteroid insufficiency (CIRCI). Currently the 250 µg cosyntropin stimulation test is the preferred diagnostic test for CIRCI. Few papers explored the role of the 1 µg cosyntropin test in septic shock patients. In this study, we compared both tests in septic shock patients taking a special interest in the population with intermediary baseline cortisol. Prospective noninterventional study included 74 septic shock patients. After measurement of baseline cortisol all patients received 1 µg of cosyntropin i. v. and 4 h later 249 µg of cosyntropin. We compared the cortisol increase after each test and its relation to mortality and vasopressor therapy. There was a moderate correlation in response to low and high dose cosyntropin, r(s)=0.55. This correlation in patients with baseline cortisol between 10-34 µg/dl is, r(s)=0.67. The increase induced by both tests was equally accurate to identify mortality and time of vasopressor withdrawal. Low and high dose cosyntropin tests presented a moderate correlation in patients with baseline cortisol between 10-34 µg/dl. Both tests are equally accurate to identify mortality and time of vasopressor therapy. These results suggest that both tests could be used to diagnose CIRCI.

Assessing adherence to objective disease monitoring and outcomes with adalimumab in a real-world IBD cohort.

BACKGROUND: Data suggests that tight objective monitoring may improve clinical outcomes in IBD. AIM: To assess the adherence to serial tight objective monitoring(clinical and biomarkers) and its effect on clinical outcomes. METHODS: We retrospectively reviewed the chart of 428 consecutive IBD patients started on adalimumab between January 1,2015-January 1,2019 [338 Crohn's disease(CD), 90 ulcerative colitis(UC)]. Clinical symptoms(assessed by Harvey-Bradshaw-Index,partial Mayo),C-Reactive Protein(CRP), and fecal calprotectin(FCAL) assessments were captured at treatment initiation and at 3,6,9, and12 months. Dose optimization and drug sustainability curves were plotted by Kaplan-Meier method. RESULTS: Clinical evaluation was available in nearly all patients at 3(CD-UC:95-94%), 6(90-83%), 9(86-85%) and 12(96-89%) months. CRP testing frequency decreased in CD patients over time. Compliance to serial FCAL testing was low. Clinical remission at one-year was higher in patients adherent to early assessment visit at 3 months(p = 0.001 for CD and UC). Adherence to early follow-up resulted in earlier dose optimization in CD and UC patients(pLogrank=0.026 for UC & p = 0.09 for CD). Overall drug sustainability did not differ. CONCLUSION: Clinical & CRP, but not FCAL, were frequently assessed in patients starting adalimumab. Adherence to early objective combined follow-up visits resulted in earlier dose optimization, improved one-year clinical outcomes but did not change drug sustainability.

Late holocene tectonic activity along the margins of the sinai subplate.

Remarkable folding and uplifting movements were active along the western margin of the Sinai subplate (the Bardawil Lagoon and its periphery) during the Upper Holocene. The coasts of the eastern margin (Gulf of Elat) were also uplifted during the same tectonic phase. The nature of this activity is discussed in relation to the regional tectonic framework.

The dead sea: deepening of the mixolimnion signifies the overture to overturn of the water column.

Throttling of freshwater inputs into the meromictic Dead Sea weakened the long-term stability of the water column. Between 1975 and 1978 successive deepenings of the pycnocline from 70 meters to beyond 200 meters were recorded. Complete overturn finally took place during the winter of 1978-1979. This unique process was accompanied by changes in the geochemistry of several components.

Treatment-induced remission of medulloblastoma using a chemotherapeutic regimen devoid of vincristine in a child with Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth (cmt) disease is the most common form of inherited neuropathy. Core features include peripheral neuropathy and secondary axonal degeneration, with a noted distal predominance of limb-muscle wasting, weakness, and sensory loss. Given the significant prevalence of cmt, superimposed neoplastic disease can be encountered within this patient population. Malignancies that are treated with vincristine (a microtubule-targeting agent), even at low doses as part of standard treatment, pose a significant challenge for patients with cmt. Here, we present the case of a child with cmt who was successfully treated for medulloblastoma without vincristine, a standard drug used for treatment of that disease, to avoid the risk of severe debilitating neuropathy. This report is the first of a patient successfully treated for medulloblastoma without vincristine.

Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system.

Ephrin-A5 (AL-1/RAGS), a ligand for Eph receptor tyrosine kinases, repels retinal axons in vitro and has a graded expression in the superior colliculus (SC), the major midbrain target of retinal ganglion cells. These properties implicate ephrin-A5 in the formation of topographic maps, a fundamental organizational feature of the nervous system. To test this hypothesis, we generated mice lacking ephrin-A5. The majority of ephrin-A5-/- mice develop to adulthood, are morphologically intact, and have normal anterior-posterior patterning of the midbrain. However, within the SC, retinal axons establish and maintain dense arborizations at topographically incorrect sites that correlate with locations of low expression of the related ligand ephrin-A2. In addition, retinal axons transiently overshoot the SC and extend aberrantly into the inferior colliculus (IC). This defect is consistent with the high level of ephrin-A5 expression in the IC and the finding that retinal axon growth on membranes from wild-type IC is inhibited relative to that on membranes from ephrin-A5-/- IC. These findings show that ephrin-A5 is required for the proper guidance and mapping of retinal axons in the mammalian midbrain.

Immune interferon inhibits proliferation and induces 2'-5'-oligoadenylate synthetase gene expression in human vascular smooth muscle cells.

Proliferation of vascular smooth muscle cells (SMC) contributes to formation of the complicated human atherosclerotic plaque. These lesions also contain macrophages, known to secrete SMC mitogens, and T lymphocytes. Many of the SMC in the lesions express class II major histocompatibility antigens, an indication that activated T cells secrete immune IFN-gamma locally in the plaque. We therefore studied the effect of IFN-gamma on the proliferation of cultured SMC derived from adult human blood vessels. IFN-gamma (1,000 U/ml) reduced [3H]thymidine (TdR) incorporation into DNA by SMC stimulated with the well-defined mitogens IL 1 (from 15.3 +/- 0.7 to 6.2 +/- 0.7 dpm X 10(-3)/24 h) or platelet-derived growth factor (PDGF) (from 18.5 +/- 1.0 to 7.3 +/- 0.7 dpm X 10(-3)/24 h). Kinetic and nuclear labeling studies indicated that this effect of IFN-gamma was not due to altered thymidine transport or specific radioactivity of TdR in the cell. In longer term experiments (4-16 d) IFN-gamma prevented net DNA accumulation by SMC cultures stimulated by PDGF. IFN-gamma also delayed (from 30 to 60 min) the time to peak level of c-fos RNA in IL 1-treated SMC. It is unlikely that cytotoxicity caused these effects of IFN-gamma, as the inhibition of growth was reversible and we detected no cell death in SMC cultures exposed to this cytokine. Activation of 2'-5' oligoadenylate synthetase gene expression may mediate certain antiproliferative and antiviral effects of interferons. Both IFN-gamma and type I IFNs (IFN-alpha or IFN-beta) induced 2'-5' oligoadenylate synthetase mRNA and enzyme activity in SMC cultures, but with concentration dependence and time course that may not account for all of IFN-gamma's cytostatic effect on SMC. The accumulation of SMC in human atherosclerotic lesions is a long-term process that must involve altered balance between growth stimulatory and inhibitory factors. The cytostatic effect of IFN-gamma on human SMC demonstrated here may influence this balance during human atherogenesis, because T cells present in the complicated atherosclerotic plaque likely produce this cytokine.

Interleukin 1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids.

There is much interest in defining the signals that initiate abnormal proliferation of cells in a variety of states characterized by the presence of mononuclear phagocytes. Since IL-1 is a major secretory product of activated human monocytes we examined whether this cytokine can stimulate the growth of human vascular smooth muscle cells (SMC). Neither recombinant IL-1 (rIL-1) alpha (less than or equal to 5.0 ng/ml) nor beta (less than or equal to 100 ng/ml) stimulated SMC growth during 2-d incubations under usual conditions. IL-1 did stimulate SMC to produce prostanoids such as PGE1 or PGE2 that can inhibit SMC proliferation. When prostaglandin synthesis was inhibited by indomethacin or aspirin both rIL-1 alpha and beta (greater than or equal to 1 ng/ml) markedly increased SMC growth. In longer-term experiments (7-28 d) rIL-1 stimulated the growth of SMC even in the absence of cyclooxygenase inhibitors. The addition of exogenous PGE1 or PGE2 (but not PGF1 alpha, PGF2 alpha, PGI2) to indomethacin-treated SMC blocked their mitogenic response to rIL-1. Antibody to IL-1 (but not to platelet-derived growth factor [PDGF]) abolished the mitogenic response of SMC to rIL-1. Exposure of SMC to rIL-1 or PDGF caused rapid (maximal at 1 h) and transient (baseline by 3 h) expression of the c-fos proto-oncogene, determined by Northern analysis. We conclude that IL-1 is a potent mitogen for human SMC. Endogenous prostanoid production simultaneously induced by IL-1 appears to antagonize this growth-promoting effect in the short term (2 d) but not during more prolonged exposures. IL-1 produced by activated monocytes at sites of tissue inflammation or injury may thus mediate both positive and negative effects on SMC proliferation that are temporally distinct.

Comparison of effects of 1 alpha-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 in man.

The effects of short-term treatment with 1,25-dihydroxy-vitamin D3 [1,25(0H)2D3] or 1 alpha-hydroxy-vitamin D3 [1 alpha(OH)D3] on intestinal absorption of 47Ca were compared in 41 experiments in normals and 72 experiments in patients with chronic renal failure. 11 patients were studied a second time after treatment for 2-5 mo. Doses varied from 0.14 to 5.4 mug/day to establish dose-response relationships. Urinary calcium was monitored in normal subjects, nine of whom received a constant calcium intake on a metabolic unit. There was an increase in intestinal absorption of 47Ca and urinary calcium in normals receiving 1,25 (OH)2D3, 0.14 mug/day or greater, and 0.28 mug/day or greater augmented intestinal absorption of 47Ca in chronic renal failure. In contrast, 2.6 mug/day of 1 alpha (OH) D3 was required to increase intestinal absorption of 47Ca in both groups. The increase in urinary calcium to maximal levels was delayed during treatment with 1 alpha (OH) D3, 5-10 days vs. 2-5 days with 1,25 (OH)2D3. Moreover, half times for urinary calcium to decrease to pretreatment levels after stopping treatment were greater after 1 alpha-(OH) D3 (1.5-2.7 days) than 1,25(OH)2D3 (1.1-2.0 days). With long-term administration there was a progressive increase in intestinal absorption of 47Ca in the patients receiving 1 alpha (OH)D3; this was not observed with 1,25(OH)2D3. The pharmacologic differences between 1 alpha(OH) D3 and 1,25(OH)2D3 may be explained by the requirement for 25-hydroxylation of 1alpha(OH) D3 before biologic effects occur; at low doses (less than 1 mug/day), 1 alpha(OH) D3 competes with vitamin D3 for 25-hydroxylation. With prolonged treatment or larger doses (greater than 2 mug/day),, 1alpha(OH) D3 could accumulate and then be hydroxylated resulting in production of higher levels of 1,25(OH)2D3.

Eph receptor tyrosine kinases and their ligands in neural development.

Receptor tyrosine kinases play important roles in many developmental phenomena, including the regulation of cell proliferation, differentiation, and survival. The largest subfamily of receptor tyrosine kinases are the Eph receptors, which are widely expressed in the nervous system. With the recent identification of several Eph ligands, it has become evident that Eph receptors and their ligands are involved in the guidance of retinal axons and in the process of hindbrain segmentation.

Cooperativity in the adsorption of magnetic colloidal particles.

In this paper we investigate the adsorption of magnetic particles onto magnetically patterned substrates. We find that the adsorption process is cooperative, where the probability of adsorption decreases with increasing substrate occupancy (namely, density of adsorbed particles). The effect of cooperativity can be accounted for by a simple modification of the adsorption probability as manifested by the binomial distribution. The negative cooperativity found in the magnetic particle adsorption is not due to direct repulsion between particles, but to screening of the surface's magnetic field by previously adsorbed particles. Thus, the adsorption of magnetic colloids on magnetic substrates is a self-limiting process.

Barbiturates and lung cancer in humans.

In a hypothesis-generating study looking for possible carcinogenic effects of drugs in humans, each of three barbiturates (pentobarbital sodium, phenobarbital, and secobarbital sodium) showed a statistically significant association with the subsequent development of lung cancer, with relative risks ranging from 1.5 to 2.8. Further analysis showed that the association was not explained by the increased prescription of barbiturate drugs shortly before the diagnosis of lung cancer or by an association of barbiturate use with cigarette smoking. Much of the data did not support a causal relationship. Neither a relation of lung cancer to duration or intensity of use not one between barbiturate use and a specific histologic type could be demonstrated.

Initial screening for carcinogenicity of commonly used drugs.

Computer-stored drug-dispensing data for 143,574 outpatients were used to identify users of various medicinal drugs during the 4-year period beginning in July 1969. These patients were followed through 1976 for the development of cancer. This report presents the results of screening analyses for 95 commonly used drugs and drug groups in relation to 56 primary cancer sites and combinations of sites. Statistically significant positive or negative associations with at least one site were found for 53 drugs. Some of these associations were undoubtedly due to chance sampling variation; some confirmed previous reports; some suggested interesting new hypotheses concerning possible drug effects or other etiologic or preventive factors. Further study is required before conclusions as to causality can be reached. Although the duration of follow-up in this study is relatively short so far, the absence of associations for many of the drugs studied provides some provisional assurance of their lack of carcinogenic effects.

Screening for possible drug carcinogenicity: second report of findings.

Cancer development was followed up through 1978 in 143,574 outpatients who were identified on the basis of computer-stored drug-dispensing data as users of various medicinal drugs during the 4-year period starting in July 1969. Screening analyses were repeated for the 95 most commonly used drugs and drug groups, which were reported previously after a shorter follow-up, and it was found that several drug-cancer associations had either gained or lost statistical significance since the report. Screening of 120 additional less commonly used drugs revealed one negative and 43 positive drug-cancer associations. A few of these associations suggested interesting new hypotheses about possible drug effects, but further study is required before conclusions on causality can be drawn. The absence of association with cancer for many drugs provides some provisional assurance for the absence of carcinogenicity, but further follow-up is needed to rule out later effects.

Breast cancer and serum cholesterol.

Recent studies have suggested a role for dietary fat in the etiology of breast cancer. The relation of serum cholesterol and other serum lipid measures to breast cancer incidence was investigated in a cohort of 95, 179 women who had multiphasic health checkups from 1964 through 1972. Through 1977, 1,035 new breast cancer cases occurred in over 752,000 person-years of follow-up. Age-adjusted incidence rates were 1.45, 1.37, 1.31, and 1.40/1,000 person-years from the lowest to the highest quartile of serum cholesterol level, respectively. Similarly, no statistically significant relation was detected between beta-lipoprotein or total lipids and breast cancer. The sample size was sufficiently large to have detected a relative risk of 1.4 or larger with a probability of 99.9% at the 0.05 level of significance. The expected relation od breast cancer to established risk factors was confirmed by univariate analysis, and serum cholesterol and breast cancer were not associated after simultaneous consideration of nine other risk factors by multivariate analysis. These data suggest that the postulated causal relation between dietary fat and breast cancer does not act via an effect on circulating lipid levels.