The current standard of care for high-risk melanoma patients is a two-step process using Total Bo... more The current standard of care for high-risk melanoma patients is a two-step process using Total Body Photography (TBP) followed by dermoscopy and is limited to a select group of patients. Methods: A cross-sectional study of patient characteristics and self-reported melanoma risk factors associated with TBP usage and pathology-confirmed outcomes was conducted on a sample of 4,692 patients in a single practitioner private dermatology setting. Results: TBP patients were significantly more likely to be male, partnered, tobacco users, highly educated, and have increased self-reported risk factors (such as fair skin, personal history of skin cancer or melanoma, family history of skin cancer, numerous moles, or previous history of sunburn, P<0.05). Personal history of skin cancer and melanoma, male gender, ?40 moles, Medicare insurance, and increasing age were positively associated with malignancy outcomes, whereas higher education, family history of melanoma, and traditional (private) i...
the rat heart. Neuronal regulation of the development of the alpha-adrenergic chronotropic respon... more the rat heart. Neuronal regulation of the development of the alpha-adrenergic chronotropic response in
Hypertension (HTN) is a leading global noncommunicable cause of mortality and dietary salt is the... more Hypertension (HTN) is a leading global noncommunicable cause of mortality and dietary salt is the most common modifiable risk factor for HTN. Evidence suggests that tumor necrosis factor alpha (TNF-α) modulates mechanisms that may contribute to salt-sensitive hypertension (SSHT). We conducted a secondary analysis of the baseline cohort of the DASH-Sodium trial, to explore the relationship between TNF-α and systolic blood pressure (SBP) in subjects categorized by race, sex, and baseline blood pressure. Urinary TNF-α levels adjusted for creatinine (pg/mg) were measured in (91%) (374 of 412) subjects ingesting high salt (150 mmol) and control diet for 2 weeks prior to randomization. Descriptive analyses were used to determine the sample prevalence of demographic, laboratory, and outcome variables, and bivariate analyses were used to check for highly correlated variables. Robust multiple linear regression was used to evaluate the association of TNF-α and SBP with and without covariates,...
The large-scale deployment of low-cost, noninvasive mechanisms of early detection are needed to r... more The large-scale deployment of low-cost, noninvasive mechanisms of early detection are needed to reduce the melanoma burden. A serial 2-step system could power mass screening efforts serving the uninsured and underinsured as well as the rural and remote US counties where melanoma mortality is doubled for lack of access to dermatologists. Furthermore, serial melanoma screening strategies, serial total body photography and serial digital dermatoscopy imaging may be performed as a telehealth service, and thus would be available in any location that can support activity compliant with the Health Insurance Portability and Accountability Act and has appropriate bandwidth.
Dermatoscopic features of minute melanomas (smaller than 2 mm in diameter) have been reported and... more Dermatoscopic features of minute melanomas (smaller than 2 mm in diameter) have been reported and the diagnosis in these cases relied on dermatoscopic clues. We report a minute melanoma, (1.5 mm and 0.9 mm in diameter dermatoscopically and histologically, respectively), asymmetrical but with minimal clues to malignancy, identified as a new and changing lesion over a period of 8 months by review of automated multi-camera-array total body photography (TBP) images. A 64-year-old man with a personal history of melanoma presented to a dermatologist for a routine interval-review and an evolving 1.5 mm diameter lesion on his right medial calf was identified by a melanographer. A review of a TBP image taken 8 months prior to this presentation revealed a barely visible pigmented lesion that had intensified in an image taken 4 months prior to presentation. At the time of presentation a small, darkly pigmented lesion was identified clinically (Fig. 1). Dermatoscopy (Fig. 1) revealed a 1.5 mm pigmented macule with a structureless pattern and slight asymmetry of colour. There were no compelling clues to malignancy according to published algorithms but an excisional biopsy was performed with a 2 mm punch because of a documented history of change at mature age in a highrisk individual, with no clues to a specific benign diagnosis. Dermatopathology images (Fig. 1) revealed unequivocal features of melanoma in situ. Current clinical and dermatoscopic detection depends primarily on two key clinical features, disorganization in pattern and colouration. Diagnostic algorithms have been developed that rely on two factors: the presence of asymmetry and certain defined clues including those provided by the differential colour of melanin at different depths in the skin. It is now recognised that the arbitrary designation of a diameter greater than 6 mm to the clinical diagnosis of melanoma, as in the clinical ABCD method, is inappropriate. We therefore suggest that, in the clinical ABCD method the D for diameter could be appropriately substituted with D for dynamic. Interval TBP, now recommended in the Clinical Practice Guidelines for the management of melanoma in high-risk patients in Australia and New Zealand, adds the dimension of change over time with respect to any lesion on the skin, regardless of whether it is initially of interest. The use of automated TBP, as in the case presented here (Melanoscan, Daavlin, Bryan, OH, USA), where multiple cameras capture and process simultaneously acquired images, facilitates routine, economical TBP at each clinical review. While dermatoscopy is the standard of care in the diagnosis of melanoma, the use of automated TBP in routine practice could shift the threshold of diagnosis so that Figure 1 (a) Sequential images taken over 8 months by a Melanoscan device and organised by a melanographer for the examining dermatologist. (b) Dermatoscopy revealed a structureless, brown-pigmented lesion 1.5 mm in diameter, as measured on the dermatoscope scale, with asymmetry of colour but lacking nequivocal clues to malignancy. (c) Dermatopathology revealed a melanocytic neoplasm, measuring 0.9 mm in diameter by histology, with architectural and cytological features of melanoma in situ.
Journal of Pharmacology and Experimental Therapeutics
Several actions of angiotensin II have been linked to metabolism of arachidonic acid by lipoxygen... more Several actions of angiotensin II have been linked to metabolism of arachidonic acid by lipoxygenases. To evaluate the importance of this interaction intrarenally we tested the effect of three different lipoxygenase inhibitors, BW755c (50 microM), a dual lipoxygenase-cyclooxygenase inhibitor, MK447 (200 microM), a nonselective lipoxygenase inhibitor which can stimulate cyclooxygenase, and baicalein (1 microM), a highly selective 12-lipoxygenase inhibitor, on angiotensin II-evoked hemodynamic changes in the rat isolated kidney, perfused with oncotic agents. Kidneys were pretreated with indomethacin (10 microM) to exclude participation of cyclooxygenase-dependent arachidonate products. Renal perfusion pressure was kept constant at 90 mm Hg by continuous adjustments in perfusate flow rate. Inhibition of cyclooxygenase alone produced a transient potentiation of the vasoconstrictor response to angiotensin II without altering GFR. On the other hand, the lipoxygenase inhibitors attenuated ...
In tissue culture, sympathetic neurons exert a trophic effect on myocardial cells to alter the al... more In tissue culture, sympathetic neurons exert a trophic effect on myocardial cells to alter the alpha-adrenergic response from positive to negative chronotropism. We hypothesized that this neurotrophic effect might be a result of the release of a humoral substance into the bulk phase of the culture medium by the neurons. The negative chronotropic response to alpha stimulation persisted in nerve-muscle cultures pretreated with the muscarinic antagonist atropine, indicating that acetylcholine is not the trophic agent. Further, variations in the concentration of norepinephrine, epinephrine or dopamine in the nerve-muscle culture media do not account for the presence of a negative chronotropic response to alpha stimulation. Finally, muscle cells grown in the same petri dish with innervated muscle cells, to allow conditioning of the muscle cell environment by the neurons, do not acquire a negative chronotropic response to alpha stimulation. The results of this study clearly demonstrate th...
Publisher Summary The chapter presents a study on isolation of rabbit renomedullary cells and ara... more Publisher Summary The chapter presents a study on isolation of rabbit renomedullary cells and arachidonate metabolism. Novel arachidonic acid (AA) metabolites arising from the so-called third pathway are generated by cells of the medullary thick ascending limb of Henle's loop (mTALH). Evidence for the conversion of AA through the cytochrome P -450 pathway can be attained by the following: (1) the absolute dependency of this pathway, in broken cell preparations, on the presence of NADPH; (2) inhibition of product formation by SKF 525A and other monooxygenase inhibitors; and (3) the failure of indomethacin to affect product formation. In addition to high Na + , K + -ATPase activity, mTALH cells obtained from rabbits have distinct morphological and histochemical characteristics. These epithelial cells are morphologically recognized as being 8–10 μ m in diameter, with large nuclei, numerous mitochondria, and few apical microvilli. The chapter mentions the efficient method of isolating mTALH cells by centrifugal elutriation, a procedure that separates cells according to their sedimentation rate. This method provides a more highly purified suspension (85–95%) of mTALH cells, with sufficient yield (20–30 x 10 6 ) required for the biochemical studies, than can be achieved through microdissection techniques. By using centrifugal elutriation to separate and obtain mTALH cells, it is possible to study AA metabolism by these cells in relative homogeneity, and also to establish the conditions necessary to grow them and preserve cytochrome P -450 activity in culture.
Excessive salt intake is associated with hypertension and cardiovascular morbidity. However, iden... more Excessive salt intake is associated with hypertension and cardiovascular morbidity. However, identifying those at risk of salt sensitive hypertension (SSH) remains a challenge due to its unequal distribution among populations and inaccurate assessment of dietary sodium (Na) and potassium (K) intake. The objective of this study was to compare indices of dietary Na intake in relation to systolic blood pressure (SBP) in salt sensitive (SS) and salt resistant (SR) subjects from the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial. We hypothesized that when compared to urinary Na or K independently, Na/K ratio is a better predictor of SSH when defined as a 5-10 mmHg change in SBP from low to high dietary Na. Among 404 Black and White subjects, baseline classifications included 177 SS and 227 SR. After diet randomization, on the control 107 were SS and 92 SR and on the DASH 70 were SS and 135 SR. Descriptive statistics, bivariate analysis, followed by linear regression models f...
Freshly isolated cells obtained from the medullary segment of the rabbit thick ascending limb of ... more Freshly isolated cells obtained from the medullary segment of the rabbit thick ascending limb of Henle's loop (mTALH) metabolize arachidonic acid (AA) primarily by the cytochrome P-450 monooxygenase pathway forming several products; a vasorelaxant and an inhibitor of Na+-K+-ATPase have been identified. These studies have been extended to mTALH cells in culture. The ability of cells isolated from 1-mo-old rabbits to grow in culture far surpassed that of cells isolated from adult rabbits, whereas similar cytochrome P-450-dependent AA metabolites were produced by freshly isolated cells from rabbits of both ages. Three-week-old mTALH cultures formed ouabain-sensitive "domes" when grown on plastic surfaces and developed transepithelial voltages (4.7 + 1.2 mV, n = 6) when grown on gas-permeable surfaces. Electron microscopy of the cells showed typical mTALH cell characteristics. The presence of Tamm-Horsfall protein, a surface membrane protein of mTALH cells, in 90-95% of th...
The current standard of care for high-risk melanoma patients is a two-step process using Total Bo... more The current standard of care for high-risk melanoma patients is a two-step process using Total Body Photography (TBP) followed by dermoscopy and is limited to a select group of patients. Methods: A cross-sectional study of patient characteristics and self-reported melanoma risk factors associated with TBP usage and pathology-confirmed outcomes was conducted on a sample of 4,692 patients in a single practitioner private dermatology setting. Results: TBP patients were significantly more likely to be male, partnered, tobacco users, highly educated, and have increased self-reported risk factors (such as fair skin, personal history of skin cancer or melanoma, family history of skin cancer, numerous moles, or previous history of sunburn, P<0.05). Personal history of skin cancer and melanoma, male gender, ?40 moles, Medicare insurance, and increasing age were positively associated with malignancy outcomes, whereas higher education, family history of melanoma, and traditional (private) i...
the rat heart. Neuronal regulation of the development of the alpha-adrenergic chronotropic respon... more the rat heart. Neuronal regulation of the development of the alpha-adrenergic chronotropic response in
Hypertension (HTN) is a leading global noncommunicable cause of mortality and dietary salt is the... more Hypertension (HTN) is a leading global noncommunicable cause of mortality and dietary salt is the most common modifiable risk factor for HTN. Evidence suggests that tumor necrosis factor alpha (TNF-α) modulates mechanisms that may contribute to salt-sensitive hypertension (SSHT). We conducted a secondary analysis of the baseline cohort of the DASH-Sodium trial, to explore the relationship between TNF-α and systolic blood pressure (SBP) in subjects categorized by race, sex, and baseline blood pressure. Urinary TNF-α levels adjusted for creatinine (pg/mg) were measured in (91%) (374 of 412) subjects ingesting high salt (150 mmol) and control diet for 2 weeks prior to randomization. Descriptive analyses were used to determine the sample prevalence of demographic, laboratory, and outcome variables, and bivariate analyses were used to check for highly correlated variables. Robust multiple linear regression was used to evaluate the association of TNF-α and SBP with and without covariates,...
The large-scale deployment of low-cost, noninvasive mechanisms of early detection are needed to r... more The large-scale deployment of low-cost, noninvasive mechanisms of early detection are needed to reduce the melanoma burden. A serial 2-step system could power mass screening efforts serving the uninsured and underinsured as well as the rural and remote US counties where melanoma mortality is doubled for lack of access to dermatologists. Furthermore, serial melanoma screening strategies, serial total body photography and serial digital dermatoscopy imaging may be performed as a telehealth service, and thus would be available in any location that can support activity compliant with the Health Insurance Portability and Accountability Act and has appropriate bandwidth.
Dermatoscopic features of minute melanomas (smaller than 2 mm in diameter) have been reported and... more Dermatoscopic features of minute melanomas (smaller than 2 mm in diameter) have been reported and the diagnosis in these cases relied on dermatoscopic clues. We report a minute melanoma, (1.5 mm and 0.9 mm in diameter dermatoscopically and histologically, respectively), asymmetrical but with minimal clues to malignancy, identified as a new and changing lesion over a period of 8 months by review of automated multi-camera-array total body photography (TBP) images. A 64-year-old man with a personal history of melanoma presented to a dermatologist for a routine interval-review and an evolving 1.5 mm diameter lesion on his right medial calf was identified by a melanographer. A review of a TBP image taken 8 months prior to this presentation revealed a barely visible pigmented lesion that had intensified in an image taken 4 months prior to presentation. At the time of presentation a small, darkly pigmented lesion was identified clinically (Fig. 1). Dermatoscopy (Fig. 1) revealed a 1.5 mm pigmented macule with a structureless pattern and slight asymmetry of colour. There were no compelling clues to malignancy according to published algorithms but an excisional biopsy was performed with a 2 mm punch because of a documented history of change at mature age in a highrisk individual, with no clues to a specific benign diagnosis. Dermatopathology images (Fig. 1) revealed unequivocal features of melanoma in situ. Current clinical and dermatoscopic detection depends primarily on two key clinical features, disorganization in pattern and colouration. Diagnostic algorithms have been developed that rely on two factors: the presence of asymmetry and certain defined clues including those provided by the differential colour of melanin at different depths in the skin. It is now recognised that the arbitrary designation of a diameter greater than 6 mm to the clinical diagnosis of melanoma, as in the clinical ABCD method, is inappropriate. We therefore suggest that, in the clinical ABCD method the D for diameter could be appropriately substituted with D for dynamic. Interval TBP, now recommended in the Clinical Practice Guidelines for the management of melanoma in high-risk patients in Australia and New Zealand, adds the dimension of change over time with respect to any lesion on the skin, regardless of whether it is initially of interest. The use of automated TBP, as in the case presented here (Melanoscan, Daavlin, Bryan, OH, USA), where multiple cameras capture and process simultaneously acquired images, facilitates routine, economical TBP at each clinical review. While dermatoscopy is the standard of care in the diagnosis of melanoma, the use of automated TBP in routine practice could shift the threshold of diagnosis so that Figure 1 (a) Sequential images taken over 8 months by a Melanoscan device and organised by a melanographer for the examining dermatologist. (b) Dermatoscopy revealed a structureless, brown-pigmented lesion 1.5 mm in diameter, as measured on the dermatoscope scale, with asymmetry of colour but lacking nequivocal clues to malignancy. (c) Dermatopathology revealed a melanocytic neoplasm, measuring 0.9 mm in diameter by histology, with architectural and cytological features of melanoma in situ.
Journal of Pharmacology and Experimental Therapeutics
Several actions of angiotensin II have been linked to metabolism of arachidonic acid by lipoxygen... more Several actions of angiotensin II have been linked to metabolism of arachidonic acid by lipoxygenases. To evaluate the importance of this interaction intrarenally we tested the effect of three different lipoxygenase inhibitors, BW755c (50 microM), a dual lipoxygenase-cyclooxygenase inhibitor, MK447 (200 microM), a nonselective lipoxygenase inhibitor which can stimulate cyclooxygenase, and baicalein (1 microM), a highly selective 12-lipoxygenase inhibitor, on angiotensin II-evoked hemodynamic changes in the rat isolated kidney, perfused with oncotic agents. Kidneys were pretreated with indomethacin (10 microM) to exclude participation of cyclooxygenase-dependent arachidonate products. Renal perfusion pressure was kept constant at 90 mm Hg by continuous adjustments in perfusate flow rate. Inhibition of cyclooxygenase alone produced a transient potentiation of the vasoconstrictor response to angiotensin II without altering GFR. On the other hand, the lipoxygenase inhibitors attenuated ...
In tissue culture, sympathetic neurons exert a trophic effect on myocardial cells to alter the al... more In tissue culture, sympathetic neurons exert a trophic effect on myocardial cells to alter the alpha-adrenergic response from positive to negative chronotropism. We hypothesized that this neurotrophic effect might be a result of the release of a humoral substance into the bulk phase of the culture medium by the neurons. The negative chronotropic response to alpha stimulation persisted in nerve-muscle cultures pretreated with the muscarinic antagonist atropine, indicating that acetylcholine is not the trophic agent. Further, variations in the concentration of norepinephrine, epinephrine or dopamine in the nerve-muscle culture media do not account for the presence of a negative chronotropic response to alpha stimulation. Finally, muscle cells grown in the same petri dish with innervated muscle cells, to allow conditioning of the muscle cell environment by the neurons, do not acquire a negative chronotropic response to alpha stimulation. The results of this study clearly demonstrate th...
Publisher Summary The chapter presents a study on isolation of rabbit renomedullary cells and ara... more Publisher Summary The chapter presents a study on isolation of rabbit renomedullary cells and arachidonate metabolism. Novel arachidonic acid (AA) metabolites arising from the so-called third pathway are generated by cells of the medullary thick ascending limb of Henle's loop (mTALH). Evidence for the conversion of AA through the cytochrome P -450 pathway can be attained by the following: (1) the absolute dependency of this pathway, in broken cell preparations, on the presence of NADPH; (2) inhibition of product formation by SKF 525A and other monooxygenase inhibitors; and (3) the failure of indomethacin to affect product formation. In addition to high Na + , K + -ATPase activity, mTALH cells obtained from rabbits have distinct morphological and histochemical characteristics. These epithelial cells are morphologically recognized as being 8–10 μ m in diameter, with large nuclei, numerous mitochondria, and few apical microvilli. The chapter mentions the efficient method of isolating mTALH cells by centrifugal elutriation, a procedure that separates cells according to their sedimentation rate. This method provides a more highly purified suspension (85–95%) of mTALH cells, with sufficient yield (20–30 x 10 6 ) required for the biochemical studies, than can be achieved through microdissection techniques. By using centrifugal elutriation to separate and obtain mTALH cells, it is possible to study AA metabolism by these cells in relative homogeneity, and also to establish the conditions necessary to grow them and preserve cytochrome P -450 activity in culture.
Excessive salt intake is associated with hypertension and cardiovascular morbidity. However, iden... more Excessive salt intake is associated with hypertension and cardiovascular morbidity. However, identifying those at risk of salt sensitive hypertension (SSH) remains a challenge due to its unequal distribution among populations and inaccurate assessment of dietary sodium (Na) and potassium (K) intake. The objective of this study was to compare indices of dietary Na intake in relation to systolic blood pressure (SBP) in salt sensitive (SS) and salt resistant (SR) subjects from the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial. We hypothesized that when compared to urinary Na or K independently, Na/K ratio is a better predictor of SSH when defined as a 5-10 mmHg change in SBP from low to high dietary Na. Among 404 Black and White subjects, baseline classifications included 177 SS and 227 SR. After diet randomization, on the control 107 were SS and 92 SR and on the DASH 70 were SS and 135 SR. Descriptive statistics, bivariate analysis, followed by linear regression models f...
Freshly isolated cells obtained from the medullary segment of the rabbit thick ascending limb of ... more Freshly isolated cells obtained from the medullary segment of the rabbit thick ascending limb of Henle's loop (mTALH) metabolize arachidonic acid (AA) primarily by the cytochrome P-450 monooxygenase pathway forming several products; a vasorelaxant and an inhibitor of Na+-K+-ATPase have been identified. These studies have been extended to mTALH cells in culture. The ability of cells isolated from 1-mo-old rabbits to grow in culture far surpassed that of cells isolated from adult rabbits, whereas similar cytochrome P-450-dependent AA metabolites were produced by freshly isolated cells from rabbits of both ages. Three-week-old mTALH cultures formed ouabain-sensitive "domes" when grown on plastic surfaces and developed transepithelial voltages (4.7 + 1.2 mV, n = 6) when grown on gas-permeable surfaces. Electron microscopy of the cells showed typical mTALH cell characteristics. The presence of Tamm-Horsfall protein, a surface membrane protein of mTALH cells, in 90-95% of th...
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