Human triglyceride-rich lipoprotein apo E kinetics and its relationship to LDL apo B-100 metabolism

Apolipoprotein (apo) E is a multifunctional protein that can act as a ligand for lipoprotein receptors. The receptor-mediated clearance of the triglyceride-rich lipoproteins (TRL) chylomicrons and VLDL from plasma is, in part, dependent on apo E. Enrichment of VLDL with apo E is thought to enhance receptor-mediated clearance of VLDL resulting in a low rate of conversion of VLDL to LDL. However, the kinetic mechanism controlling the concentration of apo E in VLDL is not known. We conducted kinetic studies on apo E in the TRL fraction (d < 1.006 g/ml) and apo B-100 in the TRL and LDL (d = 1.019-1.063 g/ml) fractions to assess the kinetic determinants of apo E concentration in TRL and to determine the effects that TRL apo E production and clearance rates have on the production rate of LDL apo B-100. Nineteen males between the ages of 24 and 73 underwent a primed-constant infusion with deuterated leucine tracer in the constantly-fed state. Apo B-100 from TRL and LDL, and apo E from TRL were isolated and their tracer incorporation measured by gas chromatography/mass spectrometry. The residence time and production rates of each protein were determined from the kinetic data using the SAAM II modeling program. The residence time and production rate of TRL apo E were about one-half that of TRL apo B-100 (1.8 +/- 1.0 vs. 2.9 +/- 2.1 h and 14.5 +/- 11.0 vs. 27.6 +/- 17.3 mg/kg per day, respectively). The production rate of TRL apo E was weakly correlated with the production rate of TRL apo B-100 (r = 0.424, P = 0.07). Multiple regression analysis showed that the residence time of TRL apo B-100 and the relative TRL apo E production rate (relative to the TRL apo B100 production rate) were negatively associated with LDL apo B-100 production rate, accounting for 68% of its variability. We conclude that (1) the concentration of apo E in TRL is highly correlated to its production rate, suggesting that production rate regulates the TRL apo E concentration, and (2) individuals with a relatively short TRL apo B-100 residence time and those producing TRL with a relatively low apo E content have the highest LDL apo B-100 production rates.     

Over- and Ectopic Expression of Wnt3 Causes Progressive Loss of Ameloblasts in Postnatal Mouse Incisor Teeth

Intercellular signaling is essential for the development of teeth during embryogenesis and in maintenance of the continuously growing incisor teeth in postnatal rodents. WNT intercellular signaling molecules have been implicated in the regulation of tooth development, and the Wnt3 gene shows specific expression in the enamel knot at the cap stage. We demonstrate here that Wnt3 also is expressed in specific epithelial cell layers in postnatal incisor teeth. To begin to delineate the functions of Wnt3 in developing and postnatal teeth, we determined the effects of over- and ectopic expression of Wnt3 in the tooth epithelium of mice carrying a keratin 14- Wnt3 transgene. Expression of the transgene caused a progressive loss of ameloblasts from postnatal lower incisor teeth. Loss of ameloblasts may be due to defective proliferation or differentiation of ameloblast precursors, progressive apoptosis of ameloblasts, or loss of ameloblast stem cells.     

Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss

Mohebbi N, Vargas‐Poussou R, Hegemann SCA, Schuknecht B, Kistler AD, Wüthrich RP, Wagner CA. Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss. Distal renal tubular acidosis (dRTA) is characterized by the inability to excrete acid in the renal collecting ducts resulting in inappropriately alkaline urine and hyperchloremic (normal anion gap) metabolic acidosis in the context of a normal (or near‐normal) glomerular filtration rate. Inborn dRTA can be due to autosomal dominant or recessive gene defects. Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. The majority of patients with recessive dRTA present with sensorineural hearing loss (SNHL). Few cases with abnormal widening of the vestibular aqueduct have been described with dRTA. Mutations in three different genes have been identified, namely SLC4A1, ATP6V1B1, and ATP6V0A4. Patients with mutations in the ATP6V1B1 proton pump subunit develop dRTA and in most of the cases sensorineural hearing loss early in childhood. We present two patients from two different and non‐consanguineous families with dRTA and SNHL. Direct sequencing of the ATP6V1B1 gene revealed that one patient harbors two homozygous mutations and the other one is a compound heterozygous. To our knowledge, this is the first case in the literature describing homozygosity in the same dRTA gene on both alleles.     

Nasal CPAP reduces gastroesophageal reflux in obstructive sleep apnea syndrome.

Anecdotal reports suggest that obstructive sleep apnea syndrome (OSAS) patients may suffer from frequent nocturnal gastroesophageal reflux (GER) and that nasal continuous positive airway pressure may be an effective form of antireflux therapy in this population. To confirm these clinical impressions, we performed two consecutive days of 24-h esophageal pH monitoring, nocturnal esophageal pressure recording, and polysomnography on six OSAS patients complaining of regular nocturnal GER. On night one, the patients were untreated. Five of six subjects had abnormal amounts of nocturnal GER. Arousal, movement and swallowing were more frequent (p less than 0.043) and nadir intrathoracic pressure lower (p less than 0.005) in the 30 s prior to precipitous drops in esophageal pH (greater than or equal to 2 pH units) than during random control periods. A direct association between obstructive apneas and GER was not identified. On night two, nasal CPAP was administered and successfully treated apnea in five of six subjects. In these patients, there was also dramatic reduction in GER frequency and duration on CPAP. The mean percentage of time pH less than 4 dropped from 6.3 +/- 2.1 to 0.1 +/- 0.1 percent (p less than 0.025). We believe that OSAS may predispose to nocturnal GER by lowering intrathoracic pressure and increasing arousal and movement frequency. Nasal CPAP can correct these predisposing factors and reduce GER.     

Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome)

Two kindreds with the multiple endocrine neoplasia type 2A syndrome were studied. Of one of these we examined 150 members, 20 of whom were treated with thyroidectomy for medullary carcinoma and nine with bilateral adrenalectomy for pheochromocytoma. Of the second kindred 59 members were examined, seven of whom were thyroidectomized and seven treated with bilateral adrenalectomy. Pheochromocytomas were invariably found on both sides, even in four cases in which the adrenals on one side appeared to be completely normal, not only at preoperative roentgenologic examination but also on inspection during the operation. The microscopic finding of micronodules and a cluster of abnormal medullary cells identical with those found in pheochromocytomas in one of the apparently normal adrenals represents a first stage in the development of diffuse medullary hyperplasia as well as nodular hyperplasia. This is in accordance with the fact that in the MEN type 2A syndrome pheochromocytomas are always multicentric and multiple in origin. On the basis of these findings we conclude that all patients with the MEN 2A syndrome who show symptoms and signs of active pheochromocytoma should be subjected to bilateral adrenalectomy, even when one or both of the adrenals appear to be normal at roentgenologic investigation.     

Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects

BACKGROUND. Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib.METHODS. We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR).RESULTS. Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR.CONCLUSION. These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance.TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00990808","term_id":"NCT00990808"}}NCT00990808.FUNDING. Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).     

Anal intraepithelial neoplasia and squamous cell carcinoma in HIV‐infected adults

Anal cancer is one of the most common non‐AIDS‐defining malignancies in the era of combination antiretroviral therapy. Its precursor lesion, anal intraepithelial neoplasia (AIN), is highly prevalent in HIV‐infected populations. More than 90% of anal squamous cell cancers are attributable to human papillomavirus (HPV). While the biology of HPV‐related intraepithelial neoplasia is consistent across lower anogenital sites, the natural history of AIN is not well established and cannot be assumed to be identical to that of cervical intraepithelial neoplasia. Screening strategies to prevent anal cancer should be developed based on robust natural history data in HIV‐infected and uninfected populations. Likewise, treatments need to be tested in randomized clinical trials, and reserved for those at significant risk of progression to cancer. This review covers the epidemiology, pathogenesis and immunology of HPV infection, AIN and anal cancer, and summarizes the current diagnosis, screening and treatment strategies in HIV‐infected adults.