Sickle cell disease affects between 70,000 and 90,000 individuals in the United States, the majority of whom are of African-American descent. The genetic basis of the disease is an abnormality in the β-globin gene, which causes the red blood cells to change to a “sickle” shape due to low oxygenation. The life span of patients with this disease has improved over the past few decades, although morbidity remains high. This review covers the pathophysiology of sickle cell disease and the stabilization and assessment, diagnosis and treatment, maintenance and preventive therapies, and cure of patients with sickle cell disease. Figures show hemoglobin electrophoresis; age at death for individuals with sickle cell disease in the years 1979, 1989, 1999, and 2006; sickled cells blocking blood flow; acute chest syndrome; dactylitis; and avascular necrosis. Tables list important trials, topics in need of further research, common complications, most common intravenous pain medications, and indications for transfusion. This review contains 6 highly rendered figures, 5 tables, 97 references, and a list of educational resources.

Central overexpression of leptin leads to hypertension that can be reversed by a leptin antagonist. In contrast, this leptin antagonist does not reverse the high-fat feeding-induced elevation of blood pressure, even though there is apparent blockade of other leptin-mediated metabolic and sympatho-excitatory responses.

Aging and obesity both have a significant impact on central blood pressure (BP) regulation, and previous studies indicated that changes in central redox signaling with age may affect high-fat (HF) diet-induced cardiovascular responses. Therefore, we investigated the effects of 60% HF feeding on BP regulation in young adult (5 mo) and old (26 mo) Fischer-344 × Brown-Norway rats. Radiotelemetric transmitters were implanted to measure BP, heart rate (HR), locomotor activity, and spontaneous baroreflex sensitivity. Expression and activity of NADPH oxidase and ANG II type 1 receptor were assessed in the hypothalamus and in the nucleus tractus solitarii. Old animals gained more weight on HF diet compared with young, whereas central NADPH oxidase expression and activity elevated similarly in the two age groups. After an initial hypotensive and tachycardic response during the first week of HF feeding, BP in young animals increased and became significantly elevated after 6 wk of HF feeding. In contrast, BP in old animals remained depressed. Nighttime HR and locomotor activity decreased in both young and old rats fed with HF diet, but these changes were more significant in young rats. As a result, amplitudes of circadian variation of BP, HR, and activity that were originally higher in young rats declined significantly and became similar in the two age groups. In conclusion, our experiments led to the surprising finding that HF diet has a more serious impact on cardiovascular regulation in young animals compared with old.

We examined the effect of high-fat (HF) feeding on blood pressure (BP) regulation, including hypothalamic redox signaling, as well as the changes in diurnal patterns and responses to restraint stress. Furthermore, we investigated whether HF feeding affects catecholamine and neuropeptide Y (NPY) biosynthesis in the adrenal medulla. Male obesity-prone Sprague-Dawley rats were fed with standard rat chow or 60% HF diet for 6 months. BP and heart rate (HR) were measured by telemetry, and circadian changes as well as responses to 20 min restraint stress were analyzed. Mean arterial BP was significantly elevated in HF rats both during daytime and nighttime compared with controls, whereas HR was elevated only during the day. BP and HR increased similarly in response to stress in both experimental groups; however, post-stress recovery of BP and HR were significantly delayed in HF animals. Protein levels of angiotensin II type 1 receptor (AT 1 ) and NOX2, p67 phox and p47 phox subunits of NADPH oxidase, as well as NADPH oxidase activity increased significantly in the hypothalamus with HF feeding, whereas levels of antioxidant enzymes and nitric oxide synthases remained unchanged. In addition, HF diet also elevated the adrenomedullary protein levels of tyrosine hydroxylase and NPY. This study shows that feeding obesity-prone Sprague-Dawley rats with a HF diet results in elevated BP and HR and delayed cardiovascular post-stress recovery, and that these changes are paralleled by increases in the expression and activity of NADPH oxidase in the hypothalamus without a compensatory increase in the antioxidant enzyme levels, possibly leading to superoxide-mediated sympathoexcitation and hypertension.

This study demonstrates that the role of central AngII diminishes with age in the regulation of BP both during baseline conditions and during stress, whereas the involvement of AngII in the regulation of HR remains unaffected.

Increased sympathetic nervous system (SNS) activity plays a central role in age‐related cardiovascular diseases. SNS activity is regulated in part by hypothalamic redox signaling and catecholamine biosynthesis. The aim of this study was to examine whether age affects these regulatory pathways differently in males and females. Hypothalamic and adrenomedullary protein levels were measured from young (5mo) and old (25mo) male and female F344xBN rats. NADPH oxidase p47 subunits were significantly higher in the young female (YF) compared with young male (YM) rats, and while p47 levels declined in both old male (OM) and old female (OF) rats, the reduction was smaller in OF. NADPH oxidase p67 subunit levels were similar in YM and YF, but declined more in OM than in OF. Hypothalamic CuZnSOD levels were lower in YF than in YM, and these levels further decreased with age in only males. In contrast, catalase expression was higher in YF compared with YM, and decreased more in OM than in OF. Hypothalamic tyrosine hydroxylase (TH), the rate‐limiting enzyme in catecholamine biosynthesis, was significantly higher in YM vs. YF, and decreased significantly in OM but not in OF rats. Adrenomedullary TH, an indicator of SNS activity, was similar in YF and YM, and only increased with age in males. These data show that there is a significant gender difference in how age affects central redox signaling and SNS activity.

The aim of this study was to test the role of angiotensin II (AngII)‐mediated mechanisms in age‐related changes of hypothalamic catecholamine biosynthesis, redox signaling and sympathetic nervous system (SNS) activation. Young (5 mo, n=6) and old (27 mo, n=6) F‐344xBN rats were infused intacerebroventricularly with either artificial CSF or losartan (15 µg/hour) for 3 days using osmotic minipumps. Level of hypothalamic tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine biosynthesis, decreased significantly with age, and in response to losartan both in young and old animals. In addition, MnSOD, catalase and NADPH oxidase‐p47 levels were decreased in the hypothalamus with age, and also with losartan treatment in both age groups. Adrenomedullary TH, an indicator of SNS activity, increased significantly with age, but decreased after losartan infusion in both young and old rats reversing the age‐related TH upregulation. These results suggest that central AT1 receptor signaling play an important role in the regulation of hypothalamic redox signaling and SNS regulation.

Assessments of sympathetic/parasympathetic nervous activity and baroreceptor reflex gain (BRG) are important for understanding neural mechanisms of cardiovascular diseases, and evaluation of heart rate variability (HRV) as well as spontaneous BRG from telemetric blood pressure recordings provides a useful tool in experimental rat models. We analyzed changes in these parameters in response to 60% high fat diet feeding and to central infusion of angiotensin II (AngII, 10nmol/h) or losartan (LOS, 15µg/h) in young (5 mo) and old (27mo) F344xBN rats that were equipped with telemetric BP transmitters. Spontaneous BRG was significantly higher in young rats vs. old. High fat feeding, as well as central infusions of both AngII and LOS, reduced BRG in young rats, but were ineffective in old animals. Both low frequency power (LF) of pulse interval data, which reflects sympathetic tone to the heart, and high frequency power (HF), which reflects parasympathetic tone, were significantly lower in old rats compared with young. AngII increased LF in young, but not in old rats, whereas HF remained unchanged in both groups. In contrast, LOS had no effect on either parameter. In response to high fat feeding, LF increased in young, but decreased in old rats, while HF decreased both in young and old animals. These data show that analysis of BRG and HRV can be used to detect age‐, diet‐ and AngII‐induced changes in autonomic function, and that age has a significant effect on how the autonomic nervous system reacts to these stimuli.