High Levels of Zinc‐Protoporphyrin Identify Iron Metabolic Abnormalities in Pulmonary Arterial Hypertension

Iron homeostasis influences the development of pulmonary arterial hypertension (PAH) associated with hypoxia or hematologic disorders. To investigate whether severity of idiopathic PAH (IPAH) is impacted by alterations in iron metabolism, we assessed iron metabolic markers, including levels of zinc‐protoporphyrin (Zn‐pp), transferrin receptor, and red blood cell numbers and morphology in IPAH, associated PAH and sleep apnea‐induced pulmonary hypertension patients in comparison to healthy controls and asthmatics. Despite similarly normal measures of iron metabolism, Zn‐pp levels in IPAH and sleep apnea patients were elevated approximately twofold, indicating deficient iron incorporation to form heme and levels were closely related to measures of disease severity. Consistent with high Zn‐pp, PAH patients had increased red cell distribution width (RDW). In an expanded cohort including patients with IPAH and familial disease, the RDW was validated and related to clinical parameters of severity; including pulmonary artery pressures and 6‐minute walk distances. These results reveal an increased prevalence of subclinical functional iron deficiency in primary forms of PAH that is quantitatively related to disease severity. This suggests that altered iron homeostasis influences disease progression and demonstrates the importance of closely monitoring iron status in PAH patients. Clin Trans Sci 2011; Volume 4: 253–258     

Therapy of Hypertension in African Americans

Hypertension in African Americans is a major clinical and public health problem because of the high prevalence and premature onset of elevated blood pressure (BP) as well as the high burden of co-morbid factors that lead to pharmacological treatment resistance (obesity, diabetes mellitus, depressed glomerular filtration rate, and albuminuria). BP control rates are lower in African Americans, especially men, than in other major race/ethnicity-sex groups; overall control rates are 29.9% for non-Hispanic Black men. Optimal antihypertensive treatment requires a comprehensive approach that encompasses multifactorial lifestyle modifications (weight loss, salt and alcohol restriction, and increased physical activity) plus drug therapy. The most important initial step in the evaluation of patients with elevated BP is to appropriately risk stratify them to allow determination of whether they are truly hypertensive and also to determine their goal BP levels. The overwhelming majority of African American hypertensive patients will require combination antihypertensive drug therapy to maintain BP consistently below target levels. The emphasis is now appropriately on utilizing the most effective drug combinations for the control of BP and protection of target-organs in this high-risk population. When BP is > 15/10 mmHg above goal levels, combination drug therapy is recommended. The preferred combination is a calcium antagonist/angiotensin-converting enzyme inhibitor or, alternatively, in edematous and/or volume overload states, a thiazide diuretic/angiotensin-converting inhibitor.     

Live/Real Time Three‐Dimensional Transthoracic Echocardiography in the Evaluation of Post Traumatic Acquired Thoracic Aortic Coarctation

We report a young patient with post traumatic acquired thoracic aortic coarctation in whom three‐dimensional transthoracic echocardiography (3DTTE) demonstrated incremental value over two‐dimensional transthoracic echocardiography (2DTTE). 3DTTE showed (1) en face views of the obstruction site that showed a markedly narrowed, roughly circular orifice measuring 0.33 cm² in area, (2) echogenic tissue encroaching on the graft lumen consistent with fibrosis/thrombus, and (3) no graft protrusion into the aortic lumen, only hypermobility of the medial portion of the graft. These important findings were not detected by 2DTTE. (Echocardiography 2010;27:470‐472)     

Relative bioavailability of griseofulvin lyophilized dry emulsion tablet vs. immediate release tablet: A single-dose, randomized, open-label, six-period, crossover study in healthy adult volunteers in the fasted and fed states

The oral bioavailability of griseofulvin (GF) formulated as a fast disintegrating lyophilized dry emulsion (LDE) tablet was studied and compared to the commercially available immediate release (IR) tablet, as a reference, in both the fasted and fed states in nine healthy volunteers after a single oral dose (125mg) in a crossover design. Furthermore the LDE tablets were ingested with and without water under both the fasted and fed states. In the fasted state, the rate of absorption was found to be significantly faster from LDE tablets, in the presence and absence of water, as shown by a higher C(max) (more than two times higher, p=0.0001) and a shorter t(max) (by more than 3h, p=0.0001) compared to IR tablets. The extent of absorption, expressed as AUC, from LDE tablets in the presence and absence of water was 65% and 77% larger and statistically significantly different relative to the mean AUC from IR tablets (p=0.006). In the fed state, C(max) from LDE tablets ingested with and without water was found to be about 30% and 50% higher, respectively, than the immediate release tablets. A shorter t(max) was also shown whether LDE tablets were ingested with or without water in the fed state as compared to immediate release tablets. The mean AUC from LDE tablets under fed conditions in the presence of water was about 21% larger and was not statistically significantly different from AUC from immediate release tablets (p=0.517). When ingested without water, AUC from LDE tablets was about 43% larger and statistically significantly different relative to AUC from IR tablets (p=0.033). The mean AUC from the LDE tablet ingested with water under fed conditions relative to AUC from LDE tablet ingested without water was not statistically significantly different (p=0.454). Results show that the food effect of the high fat meal is very pronounced in case of the immediate release tablets, Fulvin, than in case of LDE tablets whether given with or without water.     

Incubation in tissue culture media allows isolated rabbit proximal tubules to regain in-vivo-like transport function: response of HCO3 – absorption to norepinephrine

Using a new stop-flow perfusion technique with microspectrofluorometric determination of luminal fluid pH, we have studied which substrates or incubation conditions allow isolated rabbit proximal tubules to attain in-vivo-like rates of HCO3- absorption (J(HCO3)) and maximal responses of J(HCO3) to norepinephrine (NE). Essentially three incubation media were tested: plasma-like HCO(3-)-Ringer solution containing 5 mmol/l D-glucose (G-Ringer sol.), the same solution also containing 10 mmol/l lactate and 5 mmol/l L-alanine, (LAG-Ringer sol.), and two tissue culture media (DMEM and RPMI 1640). Compared to G-Ringer sol., application of LAG-Ringer sol. in the bath and/or lumen, or application of DMEM or RPMI 1640 in the bath either slightly increased or decreased J(HCO3) with borderline significance. However, RPMI 1640 plus 1 mmol/l pyruvate stimulated J(HCO3) by 55%. While NE (10(-5) mol/l), if applied in G-Ringer sol., had no effect, in the presence of LAG-Ringer sol. it increased J(HCO3) by approximately =40%, and in the presence of DMEM or RPMI 1640 it increased J(HCO3) by approximately =100%. This stimulation by NE followed Michaelis-Menten kinetics with an EC50 value of 0.25 micromol/l and was probably mediated by alpha1-adrenergic receptors. Additional cell pH measurements suggest that NE stimulates the basolateral Na+-HCO3- cotransporter which then becomes susceptible to inhibition by cAMP. We conclude that incubation in tissue culture media allows isolated proximal tubules to maintain a better functional state than the commonly used solutions with unphysiologically high substrate concentrations.     

Allele and genotype frequencies of polymorphic DCP1, CETP, ADRB2, and HTR2A in the Egyptian population

OBJECTIVE: The goal of this study was to determine the frequencies of important allelic variants of two drug targets, dipeptidyl carboxypeptidase ( DCP1) and cholesteryl ester transfer protein ( CETP), and two other drug receptors, beta-2 adrenergic receptor ( ADRB2) and 5-hydroxy tryptamine 2A receptor ( HTR2A), in the Egyptian population and compare them with the frequencies in other ethnic populations. METHODS: A sensitive real-time polymerase chain reaction assay was developed and successfully applied for genotyping of the consensus (wild-type) alleles plus five variants of four genes: DCP1 [the insertion allele ( I) versus the deletion allele ( D)], CETP*TaqI ( B1 versus B2), ADRB2*R16G, ADRB2*Q27E, and HTR2A*102T>C. This study was carried out in 242 unrelated Egyptian subjects and is the first to describe these allelic variants in the Egyptian population. RESULTS: The frequencies of the tested alleles were found as: DCP1 ( I: D, 0.32:0.68), CETPTaqI ( B1: B2, 0.65:0.35), ADRB2*R16G ( Arg16: Gly16, 0.57:0.43), ADRB2*Q27E ( Gln27: Glu27, 0.76:0.24), and HTR2A*102T>C ( T102: C102, 0.53:0.47). The common Arabian ancestors of the Egyptians, Spanish, Saudi, and Emirate had created a common pattern of distribution of some allelic variants ( DCP1 and CETP). However, in the genotyping of ADRB2, the frequency of the polymorphism at codon 16 was found to be similar to the Chinese population, whereas that at codon 27 was similar to African-Americans with significant differences than other Caucasian populations. The frequency of the HTR2A*102T>C variant appeared to be similar to many Caucasian populations and African-Americans. CONCLUSIONS: We have explored the frequencies of important allelic variants DCP1, CETP, ADRB2, and HTR2A among the Egyptian population focusing on the ethnic diversity in the distribution of the tested mutant alleles. Our results may help in better understanding the observed ethnic variation in angiotensin-converting enzyme inhibition and atherosclerosis therapy. It also may contribute to better characterization of interethnic differences in isoprenaline and clozapine response, which will have implications for the cost effective and rational prescribing of these drugs.     

Men's health promotion by general practitioners in a workplace setting

ABSTRACT: A project to promote men's health through diabetes education and screening was undertaken throughout rural industries in 1999/2000 in the south-west of Western Australia. Five hundred and twenty-five men aged 40–65 years participated from 27 industries. Sixty-four per cent of these men were identified at high-risk of developing diabetes and were referred to their general practitioner (GP) for follow-up. Seventy-six per cent of those at-risk visited their GP and hence the strategy adopted has been appropriate in engaging men in the preventive concept of seeking care, that is, getting them to attend their GP when they only have the risk factors but not the disease. However, men were left short of knowing how to achieve a change in their lifestyle behaviour and take appropriate action. Given the constraints of rural practice and the need to prioritise those with disease and gaps in service provision for both health services and GPs, there are two challenges: identifying those at-risk and modifying their behaviour.     

Cetuximab and irinotecan interact synergistically to inhibit the growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice.

PURPOSE: Anaplastic thyroid carcinoma (ATC) remains one of the most lethal known human cancers. Targeted molecular therapy with cetuximab, a monoclonal antibody against epidermal growth factor receptor, offers new treatment potentials for patient with ATC. Cetuximab has also been reported to have synergistic effects when combined with irinotecan, a topoisomerase inhibitor. Therefore, we hypothesized that cetuximab and irinotecan would be effective in inhibiting the growth and progression of ATC in a murine orthotopic model. EXPERIMENTAL DESIGN: The in vitro antiproliferative effects of cetuximab and irinotecan on ATC cell line ARO were examined. We also studied the in vivo effects of cetuximab and irinotecan on the growth, invasion, and metastasis of orthotopic ATC tumors in nude mice. The in vivo antitumor efficacy of cetuximab/irinotecan combination was also compared with that of doxorubicin. RESULTS: Cetuximab alone did not show any antiproliferative or proapoptotic effect on this cell line. However, when combined with irinotecan, cetuximab potentiated the in vitro antiproliferative and proapoptotic effect of irinotecan. Cetuximab, irinotecan, and cetuximab/irinotecan combination resulted in 77%, 79%, and 93% in vivo inhibition of tumor growth, respectively. Incidences of lymph node metastasis, laryngeal invasion, and tumor microvessel density were also significantly decreased in these treatment groups. Furthermore, the cetuximab/irinotecan combination was significantly more effective than doxorubicin in inhibiting the growth of orthotopic ATC xenografts. CONCLUSIONS: Combination therapy with cetuximab/irinotecan inhibits the growth and progression of orthotopic ATC xenografts in nude mice. Given the lack of curative options for patients with ATC, combination therapy with cetuximab and irinotecan treatment warrants further study.     

The long-term hospitalization experience following military service in the 1991 Gulf War among veterans remaining on active duty, 1994–2004

Background  

Despite more than a decade of extensive, international efforts to characterize and understand the increased symptom and illness-reporting among veterans of the 1991 Gulf War, concern over possible long-term health effects related to this deployment continue. The purpose of this study was to describe the long-term hospitalization experience of the subset of U.S. Gulf War veterans still on active duty between 1994 and 2004.