Interactions between leptin and the human sympathetic nervous system

Results from animal experimentation suggest a 2-way interaction between leptin and the sympathetic nervous system, with leptin causing sympathetic activation and conversely, with the sympathetic system exercising regulatory feedback inhibition over leptin release. We have now tested this hypothesis in humans. In the absence of results from leptin infusions, to test for sympathetic stimulation of leptin release, we sought a quantitative naturalistic linkage of sympathetic activity with leptin plasma concentration across a broad range of leptin values in men of widely differing adiposity. Renal norepinephrine spillover was correlated with plasma leptin (r=0.628, P<0.01), but other measures of sympathoadrenal function did not. To test for sympathetic and adrenomedullary inhibition of leptin release, we studied clinical models of high sympathetic tone, heart failure, and essential hypertension, in which lowered plasma leptin levels might have been expected but were not found; a model of low sympathetic activity, pure autonomic failure, in which plasma leptin level was normal (6.1+/-1.2 vs 12.8+/-3.1 ng/mL in healthy subjects); and a clinical model of reduced epinephrine secretion, healthy aging, in which plasma leptin level again was normal (5.7+/-1.1 ng/mL vs 4.0+/-0.9 ng/mL in men >60 years and <35 years, respectively). Paradoxically, leptin concentration was elevated in heart failure, caused entirely by reduced renal clearance of leptin release, 142.0+/-30.5 mL/min, compared with 56.9+/-18.9 mL/min (P<0.05). These results provide some support for the view that leptin stimulates the sympathetic nervous system, at least for renal sympathetic outflow, but do not confirm the concept of regulatory feedback inhibition of leptin release by the sympathetic nervous system.     

An elevated C-reactive protein level in an inpatient rehabilitation setting after joint replacement: To act or not to act? – that is the question

C-reactive protein (CRP) is part of a battery of “routine bloods” performed by residents on patients when they are admitted into a rehabilitation unit. Generally, an elevated CRP is considered to be an indicator of an acute infective process. Numerous studies have indicated that the CRP peaks on the 2nd or 3rd day post total hip arthroplasty (THR) and total knee arthroplasty (TKR) and returns to normal by day 7. When the CRP level remains elevated, it is generally felt that infection should be excluded.We performed a prospective study on 45 consecutive patients admitted into a rehabilitation unit post hip and knee arthroplasty over a 6 months period, to evaluate the incidence of an elevated CRP on admission, to determine whether an isolated elevated CRP on admission to a rehabilitation setting should not be considered as an indicator of an infective process.We found all patients (100%) had elevated CRP''s on admission, ranging from 8.6 mg/L to 139.2 mg/L, between days 5–7 post-operatively. By day 14, CRP''s reduced, but 91% of patients still had elevated CRP''s, ranging from 2.1 mg/L to 47.3 mg/L after THR and 4.8 mg/L to 40 mg/L after TKR at day 14.These results suggest that even in uncomplicated elective joint arthroplasty, CRP''s can remain elevated up to 14 days post-procedure, in the absence of an infective process.An isolated elevated CRP on admission to a rehabilitation setting should not be considered as an indicator of an infective process, but rather part of the normal post-operative inflammatory response. The elevated CRP should be monitored and only an upward trend requires further investigation and management.     

Patent foramen ovale in a large population of ischemic stroke patients: diagnosis, age distribution, gender, and race

BACKGROUND: Patent foramen ovale (PFO) is a well-recognized risk factor for ischemic strokes. The true prevalence of PFO among stroke patients is still under debate. Transesophageal echocardiography (TEE) is the "gold standard" in diagnosing PFO but the physiology requires right-to-left atrial shunting. In this report, we evaluate the prevalence of PFO in a diverse group of ischemic stroke patients studied by TEE. METHODS: TEE of 1,663 ischemic stroke patients were reviewed for cardiac source of embolism, including PFO and atrial septal aneurysm (ASA). Agitated saline bubble injection was performed to look for right to left atrial shunting. Success of maneuvers to elevate right atrial pressure (RAP) was noted by looking at the atrial septal bulge. RESULTS: Among 1,435 ischemic stroke patients analyzed, the presence or absence of PFO could not be determined in 32.1% because bulging of the septum could not be demonstrated in patients with negative contrast study despite aggressive maneuvers to elevate RAP. Of the remaining 974 patients, 294 patients (30.2%) had a PFO. The mean age was 61.5 years in both groups, with a bimodal distribution of PFO and the highest prevalence occurring in < or =30-year-old group. Prevalence of PFO was similar in men (32.4%) and women (28.15%, P = 0.15); and in Caucasian (32.1%) and African American (27.7%; P = 0.15). ASA was present in 2.02% and hypermobile septum in 2.49% of the 1,435 patients. PFO was seen in 79.3% of the patients with ASA. CONCLUSION: Successful elevation of RAP cannot be achieved in a significant number of patients undergoing TEE and determination of PFO may be difficult. In our series, the true prevalence of PFO among ischemic stroke patients was 30.2% taking into account only those patients who showed no shunting despite bulging of the atrium septum into the left atrium (PFO absent group) during the contrast study. There was no gender or racial difference in the prevalence of PFO, but there was a bimodal distribution in prevalence with age.     

High frequency of hepatitis B virus infection in patients with beta-thalassemia receiving multiple transfusions

BACKGROUND AND OBJECTIVES: Hepatitis B virus (HBV) may occasionally be transmitted through transfusion of blood units that are hepatitis B surface antigen (HBsAg) negative but HBV DNA positive. Children with beta-thalassemia are particularly susceptible to HBV because they receive multiple blood transfusions. These children have high infection rates despite vaccination against HBV. Post-vaccination infections may be a result of viruses harbouring surface (S)-gene mutations (e.g. G587A) in a region critical for reactivity to antibody to hepatitis B surface antigen (anti-HBs). The true prevalence of HBV in individuals with beta-thalassemia has not been studied previously. PATIENTS AND METHODS: Seventy patients with beta-thalassemia (median age 6 years; range 8 months to 22 years; 49 male), who had received seven to 623 (median 61) units of blood each and three doses (10/20 micro g) of HBV vaccine (Engerix B) before presentation to us, were included in the study; 50 of the 70 patients had received transfusions prior to vaccination. Enzyme-linked immunoassay for serological markers [HBsAg, antibody to hepatitis B core antigen (anti-HBc) and quantitative anti-HBs] and polymerase chain reaction (PCR) followed by Southern hybridization for molecular detection of hepatitis B, was performed on all samples. The PCR-amplified product was cloned, sequenced and the nucleotide and deduced amino acid sequences for the HBV S and polymerase (P) genes were analysed for mutations. RESULTS: Four of 70 (5.7%) individuals with beta-thalassemia were HBsAg positive and 14 (20%) were anti-HBc positive. The prevalence of serological markers increased with number of transfusions (P < 0.01). Of 70 patients, 53 (75.7%) had an anti-HBs titre of > 10 IU/l following vaccination and 17 (24.3%) were non-responders (< 10 IU/l); 22 (31.4%) of the 70 were DNA positive. The frequency of HBV infection in beta-thalassemia was similar in vaccine responders and non-responders. The virus was of subtype ayw (genotype D) in the five DNA-positive samples in which a 388-nucleotide region of the S gene was sequenced. Mutations occurred at 13 positions in the S gene and at 10 positions in the P gene. Hydrophobicity plots revealed differences in amino acid regions 117-165 and 195-211. Some of these amino acid substitutions coincided with the putative cytotoxic T-lymphocyte epitopes of both S and P proteins. CONCLUSIONS: A high frequency of HBV infection was seen using molecular methods in thalassemic patients. The frequency of infection was similar in vaccine responders and non-responders. A number of mutations were observed in the S gene, which could have implications for viral replication as well as virus-host cell interaction.