Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia.

Essentials Antiangiogenic drugs are indicated as therapies for hereditary hemorrhagic telangiectasia. We interrogated the response to four antiangiogenic drugs for anemia and intestinal bleeding. Sorafenib and a pazopanib analog significantly improved while erlotinib worsened anemia. Some oral antiangiogenic drugs were effective in reducing intestinal bleeding. SUMMARY: Background Epistaxis and gastrointestinal (GI) tract hemorrhages are common symptoms of aged hereditary hemorrhagic telangiectasia (HHT) patients that result in anemia. Clinical as well as animal studies have suggested that vascular endothelial growth factor (VEGF) neutralizing antibodies lessen hemorrhage associated with adult-onset arteriovenous malformations (AVMs). Objectives The goal of this study is to evaluate potential therapeutic effects of oral delivery of four antiangiogenic tyrosine-kinase inhibitors (TKIs) in the development of adult-onset AVMs in a murine model of HHT. Methods An adult activin receptor-like kinase 1 (Alk1)-inducible knockout (iKO) model was utilized to evaluate the effect of oral administration of sorafenib, sunitinib, erlotinib and a pazopanib analog (GW771806) on hemoglobin level, GI hemorrhages and formation of wound-induced skin AVMs. Results and Conclusions Sorafenib and GW771806 significantly improved, yet erlotinib worsened, anemia and GI-bleeding in the Alk1-iKO model. However, none of these TKIs appeared to be effective for inhibiting the development of wound-induced skin AVMs. Taken together, these results suggest that oral delivery of antiangiogenic TKIs is selectively more effective for GI bleeding than mucocutaneous AVMs, and it may provide an experimental basis for selective therapeutic options depending on the symptoms of HHT.

High-resolution spectroscopy and quantum-defect model for the gerade triplet np and nf Rydberg states of He2.

Photoionization spectra and Rydberg-state-resolved threshold-ionization spectra of the gerade triplet np Rydberg states of (4)He2 located in the vicinity of the X(+) (2)Σ(u)(+) (ν(+) = 0) ionization threshold were recorded from the 2sσ a (3)Σ(u)(+) metastable state. An accuracy of 0.01 cm(-1) was achieved for the experimental term values of the observed Rydberg states. The data were combined with spectroscopic data on low-lying triplet np and nf Rydberg states from the literature to derive energy- and internuclear-distance-dependent eigenquantum-defect parameters of multichannel quantum-defect theory (MQDT). The MQDT calculations reproduce the experimental data within their experimental uncertainties and enabled the derivation of potential-energy curves for the lowest triplet p Rydberg states (n = 2-5) of He2. The eigenquantum-defect parameters describing the p -f interaction were found to be larger than 0.002 at the energies corresponding to the high-n Rydberg states, so that the p -f interaction plays an important role in the autoionization dynamics of np Rydberg states with v(+) = 0. By extrapolating the experimental term values of triplet np Rydberg states of (4)He2 in the range of principal quantum number n between 87 and 110, the positions of the (v(+) = 0, N(+) = 3) and (v(+) = 0, N(+) = 5) levels of the ground state of (4)He(+)(2) were determined to lie 70.937(3) cm(-1) and 198.369(6) cm(-1), respectively, above the (v(+) = 0, N(+) = 1) ground rotational level.

Precision measurements of ionization and dissociation energies by extrapolation of Rydberg series: from H2 to larger molecules.

Recent experiments are reviewed which have led to the determination of the ionization and dissociation energies of molecular hydrogen with a precision of 0.0007 cm(-)1 (8 mJ/mol or 20 MHz) using a procedure based on high-resolution spectroscopic measurements of high Rydberg states and the extrapolation of the Rydberg series to the ionization thresholds. Molecular hydrogen, with only two protons and two electrons, is the simplest molecule with which all aspects of a chemical bond, including electron correlation effects, can be studied. Highly precise values of its ionization and dissociation energies provide stringent tests of the precision of molecular quantum mechanics and of quantum-electrodynamics calculations in molecules. The comparison of experimental and theoretical values for these quantities enable one to quantify the contributions to a chemical bond that are neglected when making the Born-Oppenheimer approximation, i.e. adiabatic, nonadiabatic, relativistic, and radiative corrections. Ionization energies of a broad range of molecules can now be determined experimentally with high accuracy (i.e. about 0.01 cm(-1)). Calculations at similar accuracies are extremely challenging for systems containing more than two electrons. The combination of precision measurements of molecular ionization energies with highly accurateab initio calculations has the potential to provide, in future, fully reliable sets of thermochemical quantities for gas-phase reactions.

Effect of eCG or eCG Plus hCG on oestrus expression and ovulation in prepubertal gilts.

To meet weekly breeding targets, it is occasionally necessary to inject exogenous gonadotrophins to induce oestrus in prepubertal gilts. However, the gilt oestrus response to equine chorionic gonadotrophin (eCG) either alone or in combination with human chorionic gonadotrophin (hCG) can be unpredictable. The objective of the present study was to examine possible reasons for this unpredictability. Prepubertal gilts (90 kg and 153 days of age, n = 109) received an injection of either 600 IU eCG or a combination of 400 IU eCG and 200 IU hCG (PG600), or were non-injected controls, and were then exposed to a mature boar for 15 min daily for 7 days for oestrus detection. At the time of injection, real-time ultrasound revealed that the gilt ovaries had primarily 1-2 mm follicles. Blood samples were obtained at time of hormone injection (day 0) and at days 3, 7 and 10 for assay of serum progesterone concentrations. The oestrus responses by 7 days were 15.5%, 73.3% and 0%, for eCG, PG600, and control gilts, respectively (p < 0.001). The oestrus response improved (p < 0.05) with increasing body weight. Based on circulating progesterone levels, all oestrous gilts ovulated except for four of the PG600 gilts. Failure to express oestrus in PG600 gilts was not associated with a premature rise in progesterone.

Effect of hCG treatment on the oestrous and ovulation responses to FSH in prepubertal gilts.

To ensure sufficient numbers of pregnant females, particularly at hotter times of the year, hormonal induction of gilt oestrus may be necessary. However, the gilt oestrus and ovulation responses to gonadotrophin treatment have often proven unpredictable. The objective of this study was to examine possible reasons for this unpredictability. Prepubertal gilts (approximately 150 days of age, n = 63) were assigned to one of three treatments: injection of 300 IU hCG (n = 15); pre-treatment with 100 mg FSH in polyvinylpyrrolidinone administered as 2 x 50 mg injections 24 h apart, followed by 600 IU eCG at 24 h after the second FSH injection (n = 23); or FSH pre-treatment as above followed by 300 IU hCG at 24 h after the second FSH injection (n = 25). To facilitate oestrus detection, gilts were exposed to a mature boar for 15 min daily for 7 days. Blood samples were obtained on the day of eCG or hCG injection and again 10 days later and gilt ovulation responses determined based on elevated progesterone concentrations. The oestrus responses by 7 days were 6.7%, 17.5% and 64.0% for gilts treated with hCG, FSH + eCG and FSH + hCG, respectively (p < 0.001). The oestrous gilt receiving hCG alone and one oestrous FSH + hCG gilt did not ovulate, all other oestrous gilts ovulated. A further two anoestrous FSH + eCG-treated gilts ovulated. These data suggest that FSH pre-treatment facilitated the development of ovarian follicles to the point where they became responsive to hCG, but had little effect on the response to eCG.

Effect of prior FSH treatment on the estrus and ovulation responses to eCG in prepubertal gilts.

The objective of this study was to determine the effect of pre-treatment of prepubertal gilts with FSH on the estrus and ovulatory responses to eCG injection at two ages. A total of 149 prepubertal Hypor gilts were selected at 150 days (n=76) or 180 days (n=73) of age and assigned to injection of 400 IU eCG plus 200 IU hCG (PG600), 600IU eCG alone (Folligon), pre-treatment with 72 mg FSH (Folltropin) administered as 6 x 12 mg injections at 12 h intervals with 600 IU Folligon 12h after last FSH injection, or non-injected controls. To facilitate detection of estrus, gilts were exposed to a mature boar for 15 min daily for 7 days. To determine ovulatory responses, blood samples were obtained on the day of injection and 10 days later and assayed for progesterone content. Following treatment at 150 days, one control gilt (5.3%) was deemed estrus but ovulation did not occur. Compared to treatment with Folligon alone, PG600 injection tended (P=0.1) to increase the estrus response (52.6% compared with. 26.3%) and increased (P<0.01) the ovulatory response (89.5% compared with. 47.4%). The estrous response in gilts pretreated with Folltropin was intermediate (42.1%) but the ovulatory response (47.4%) was the same as for Folligon alone. Following treatment at 180 days, two control gilts (10.5%) were deemed estrus and ovulation did occur in these gilts. There was no difference between hormone-treated groups for estrus or ovulatory responses, although the ovulatory response of PG600-treated gilts tended (P=0.1) to be greater than for the Folligon-treated group (89.5% compared with 66.7%), with Folltropin-pretreated gilts being intermediate (76.5%). These data demonstrate that the estrus and ovulatory responses of gilts were greater for PG600 than for Folligon and that while responses to PG600 were not affected by gilt age, for the combined Folligon groups, estrous response (P<0.02) and ovulatory response (P<0.05) improved with increased gilt age.

Effect of insemination-ovulation interval and addition of seminal plasma on sow fertility to insemination of cryopreserved sperm.

In swine, the use of frozen-thawed (FT) sperm for artificial insemination (AI) is limited because of poor sow fertility, possibly associated with a post-thaw capacitation-like status resulting in fewer fully viable sperm. Sow fertility to AI with FT sperm may improve with deeper deposition of sperm within the female tract, insemination very close to ovulation, or reversal of cryocapacitation by seminal plasma (SP). We performed two experiments to examine these suggestions. In experiment 1, 122 multiparous Yorkshire sows received 600 IU equine chorionic gonadotrophin at weaning and 5 mg pLH 80 h later to control time of ovulation. The predicted time of ovulation (PTO) was 38 h after pLH injection. Thereafter, sows were assigned on the basis of parity to a single AI of FT sperm at 2 h before PTO, or at 12 h before PTO, or FT sperm supplemented with 10% SP at 12 h before PTO. Control sows received fresh semen at 12 h before PTO. All semen doses were adjusted to 3 x 10(9) live cells and deposited into the cervix. Experiment 2 employed 99 multiparous crossbred sows and repeated the treatments of experiment 1 except that all FT inseminations were intrauterine. In both experiments, farrowing rates were lower (p < 0.01) following FT inseminations with no effect of time of insemination or of supplemental SP. In experiment 1, litter size was smaller following FT insemination (p < 0.05), but no effect on litter size was evident in experiment 2. Supplemental SP had no effect on litter size in either experiment. The lack of effect of either SP or timing of FT insemination on sow fertility suggests that the non-lethal sperm cryoinjury affecting fertility involves more than just cryocapacitation.

Effect of sperm cryopreservation and supplementing semen doses with seminal plasma on the establishment of a sperm reservoir in gilts.

Frozen-thawed (FT) boar sperm have a reduced fertile life, due in part to a capacitation-like status induced by cooling. Reversal of this cryocapacitation in vitro by exposure to boar seminal plasma (SP) has been demonstrated. The objective of these studies was to determine the effect of SP on the ability of FT sperm to create an oviductal sperm reservoir following artificial insemination (AI). In Experiment one, 35 pre-pubertal gilts were injected (IM) with 400 IU eCG plus 200 IU hCG to induce oestrus. At detection of oestrus, gilts were inseminated with 3 x 10(9) live sperm, either fresh (FS; n = 13), FT (n = 10), or FT supplemented with 10% v/v SP (n = 12). Gilts were killed 8 h later, their reproductive tracts recovered and the uterotubal junctions (UTJs) flushed to recover sperm. Fewer (p < 0.01) sperm were recovered following FT, compared to FS, inseminations, and there was no evident effect of SP. In Experiment two, 30 pre-pubertal gilts received IM injections of 1000 IU eCG followed by 5 mg pLH 80 h later to control time of ovulation. Gilts were inseminated with 3 x 10(9) live FS sperm (n = 6), FT sperm (n = 15) or FT sperm plus 10% SP (n = 9) at 12 h before ovulation and then sacrificed 8 h later. The UTJs were dissected and flushed for sperm recovery. Fewest (p < 0.001) sperm were recovered following FT insemination and there was no evident effect of SP. These data demonstrate that the size of the sperm reservoir is markedly reduced in gilts inseminated with FT sperm. However, the lack of effect of SP suggested that either it did not reverse cryocapacitation or that such a reversal does not impact the in vivo ability to create a sperm reservoir.

Effect of cooling and seminal plasma on the capacitation status of fresh boar sperm as determined using chlortetracycline assay.

Insemination of sows with frozen-thawed spermatozoa results in lower fertility, in part due to spermatozoa having undergone a capacitation-like reaction. The present study employed chlortetracycline (CTC) staining analysis to investigate the effect of adding 20% (v/v) boar seminal plasma (SP) to boar spermatozoa on the temporal progress of capacitation and the acrosome reaction in spermatozoa cooled to 5 degrees C or incubated at 39 degrees C. Based on CTC staining patterns, seminal plasma appeared to reverse capacitation in spermatozoa that had undergone capacitation while incubated at 39 degrees C in a capacitation-supporting medium from 59.7 to 36.6% capacitated (P<0.001). Similarly, the addition of SP to boar spermatozoa cooled to 5 degrees C resulted in both the prevention of the capacitation-like reaction, and the reversal of an established capacitation-like reaction from 63.3 to 34.2% capacitated (P<0.001). These observations indicated that some constituent(s) of boar SP both prevent spermatozoa from undergoing capacitation as well as reverse capacitation in spermatozoa that have already undergone the process.

C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) may persist due to structural changes in the atria that are promoted by inflammation. C-reactive protein (CRP), a marker of systemic inflammation, predicts cardiovascular events and stroke, a common sequela of AF. We hypothesized that CRP is elevated in patients with atrial arrhythmias. METHODS AND RESULTS: Using a case-control study design, CRP in 131 patients with atrial arrhythmias was compared with CRP in 71 control patients. Among arrhythmia patients, 6 had frequent atrial ectopy or tachycardia, 86 had paroxysmal AF, 39 had persistent AF lasting >30 days, and 70 had lone arrhythmias. CRP was higher in arrhythmia than in control patients (median, 0.21 versus 0.096 mg/dL; P<0.001). Arrhythmia patients in AF within 24 hours before sampling had higher CRP than those in sinus rhythm (0.30 versus 0.15 mg/dL; P<0.001). CRP in controls was not different than in patients with atrial ectopy or tachycardia. Lone arrhythmia patients had a CRP of 0.21 mg/dL, which was not significantly lower than arrhythmia patients with structural heart disease (CRP, 0.23 mg/dL) but higher than controls (P=0.002). Persistent AF patients had a higher CRP (0.34 mg/dL) than paroxysmal AF patients (0.18 mg/dL; P=0.008); both groups had higher CRP levels than controls (P

The effect of subclinical Mycobacterium paratuberculosis infection on milk production in Michigan dairy cows.

The objective of this study was to determine the effect of subclinical Mycobacterium paratuberculosis infection on mature equivalent milk, protein, and fat production in a sample of Michigan dairy herds with a history of cows positive for M. paratuberculosis diagnosed by fecal culture. A prospective two-group cohort study was conducted. Participating herds were tested, and productivity and reproduction records were monitored for 18 mo. All cows aged 24 mo and greater were tested for M. paratuberculosis infection using the ELISA and radiometric fecal culture (RFC) techniques. Using both tests in parallel, the overall sample apparent prevalence for M. paratuberculosis infection was 41.8%. Adjusting for diagnostic sensitivity and specificity resulted in a calculated sample true prevalence of 59.9%. Subclinical paratuberculosis test-positive status had no statistically significant effect on mature equivalent milk, fat, or protein production. The results of this study concur with the findings of other studies, reporting that the magnitude and direction of the association between subclinical paratuberculosis infection and milk production depends upon the parity of the animal, stage of disease, and the stage in lactation being monitored. Assessment of the impact of subclinical paratuberculosis on milk production must consider the average parity of the sample population. In herds that have an average parity of 2 or less, subclinical paratuberculosis infection may have little impact on milk production.

Association between myeloperoxidase levels and risk of coronary artery disease.

CONTEXT: Myeloperoxidase (MPO), a leukocyte enzyme that promotes oxidation of lipoproteins in atheroma, has been proposed as a possible mediator of atherosclerosis. OBJECTIVE: To determine the association between MPO levels and prevalence of coronary artery disease (CAD). DESIGN, SETTING, AND PATIENTS: Case-control study conducted from July to September 2000 in a US tertiary care referral center, including 158 patients with established CAD (cases) and 175 patients without angiographically significant CAD (controls). MAIN OUTCOME MEASURES: Association of MPO levels per milligram of neutrophil protein (leukocyte-MPO) and MPO levels per milliliter of blood (blood-MPO) with CAD risk. RESULTS: Leukocyte- and blood-MPO levels were both significantly greater in patients with CAD than in controls (P<.001). In multivariable models adjusting for traditional cardiovascular risk factors, Framingham risk score, and white blood cell counts, MPO levels were significantly associated with presence of CAD, with an OR of 11.9 (95% CI, 5.5-25.5) for the highest vs lowest quartiles of leukocyte-MPO and an OR of 20.4 (95% CI, 8.9-47.2) for the highest vs lowest quartiles of blood-MPO. CONCLUSIONS: Elevated levels of leukocyte- and blood-MPO are associated with the presence of CAD. These findings support a potential role for MPO as an inflammatory marker in CAD and may have implications for atherosclerosis diagnosis and risk assessment.

Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis.

BACKGROUND: Recent studies have supported the hypothesis that calcific aortic stenosis is the product of an active inflammatory process, with similarities to atherosclerosis. We sought to determine whether therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) might slow the progression of aortic stenosis. METHODS AND RESULTS: A retrospective study of 174 patients (mean age 68+/-12 years) with mild to moderate calcific aortic stenosis was conducted. Patients required normal left ventricular function, /=2 echocardiograms performed at least 12 months apart. Fifty-seven patients (33%) received treatment with a statin; the remaining 117 (67%) did not. The statin group was older and had a higher prevalence of hypertension, diabetes mellitus, and coronary disease. During a mean follow-up of 21 months, patients treated with statin had a smaller increase in peak and mean gradient and a smaller decrease in aortic valve area. When annualized, the decrease in aortic valve area for the nonstatin group was 0.11+/-0.18 cm(2) compared with 0.06+/-0.16 cm(2) for those treated with a statin (P=0.03). In multivariate analysis, statin usage was a significant independent predictor of a smaller decrease in valve area (P=0.01) and a lesser increase in peak gradient (P=0.02). CONCLUSIONS: Statin-treated patients, despite a higher risk profile for progression, had reduced aortic stenosis progression compared with those not treated with a statin. These data provide justification for a prospective randomized trial to substantiate whether statin therapy slows the progression of aortic stenosis.

Targeting triglycerides as prognostic indicators and determining lowest values for patient benefit.

A number of reports demonstrate the importance of serum triglyceride values in predicting the clinical onset of vascular disease. However, adjustment for measurements highly correlated with triglyceride (TG) levels, such as history of diabetes, body mass index, and high-density lipoprotein cholesterol (HDL-C), lessen if not remove the TG contribution to outcomes. More recently, improved analytic approaches have more persuasively implicated triglycerides as independently relevant to the onset of cardiovascular disease. Elevated TG values are the consequence of larger TG-rich particles, including very low density lipoprotein and atherogenic intermediate particles, which are in turn associated with dense low-density lipoprotein. It has been observed that a reduction in TG concentrations often proceeds in parallel with improved clinical outcomes; however, direct correlation between the two has been elusive. This has been demonstrated in multiple pharmacologic trials. However, an improvement in these relationships has been observed when TG-correlated measurements of intermediate particles, low-density lipoprotein density, and HDL-C have been made. National guidelines for cholesterol treatment have now incorporated a TG greater than 200 mg/dL as a secondary treatment trigger, which targets apolipoprotein B-related particles, represented by non-HDL-C (total cholesterol minus HDL-C), as the suggested goal of therapy.

Using the new cholesterol guidelines in everyday practice.

The third Adult Treatment Panel guidelines from the National Cholesterol Education Program, released in May 2001, depart from previous guidelines in several ways. As in previous guidelines, treatment and treatment goals are based not only on lipid levels but also on the patient's risk status. The method for calculating risk, however, has been refined considerably. Patients are classified in the highest-risk group if they have any of these disorders: known coronary artery disease, diabetes mellitus, peripheral vascular disease, abdominal aortic aneurysm, carotid artery disease, or a 10-year risk of a coronary event of more than 20% (as determined by use of a scoring method).

Efficacy and short-term safety of a new ACAT inhibitor, avasimibe, on lipids, lipoproteins, and apolipoproteins, in patients with combined hyperlipidemia.

Although acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been shown to reduce lipid levels in several animal models, the safety and lipid modifying activity of any single agent in this class has not been demonstrated in humans. The safety and efficacy of avasimibe (CI-1011), a new, unique, wholly synthetic ACAT inhibitor, was evaluated in the treatment of 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia (low levels of high-density lipoprotein cholesterol [HDL-C]). Following an 8-week placebo and dietary-controlled baseline period, patients were randomly assigned to double-blind treatment with placebo, 50, 125, 250, or 500 mg avasimibe administered as capsules once daily for 8 weeks. At all evaluated doses, avasimibe treatment resulted in prompt and significant reductions (P<0.05) in plasma levels of total triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C) with mean reductions of up to 23% and 30% respectively, apparently independent of dose. No statistically significant changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C or apolipoprotein (apo) B were detected. ApoAI levels were also unchanged on all doses of avasimibe apart from the 500 mg dosage, which was associated with a significant decrease in plasma apoAI. The relevance of this latter finding in only one dosage group is not known. All doses of avasimibe were well tolerated with no resulting significant abnormalities of biochemical, hematological, or clinical parameters.

Comparison of cardiovascular risk and lipid profiles in patients undergoing aortic valve surgery versus those undergoing coronary artery bypass grafting.

BACKGROUND AND AIM OF THE STUDY: Hyperlipidemia is a risk factor for the progression of coronary artery disease, and possibly also valvular aortic stenosis. Thus, patients with aortic stenosis, coronary disease (or both) might be expected to have more abnormal lipid profiles than those without these two conditions. METHODS: The lipid profiles of patient subsets undergoing aortic valve replacement (AVR) with or without concomitant coronary artery bypass grafting (CABG), as well as those undergoing isolated CABG, between 1987 and 1997 were analyzed retrospectively. Four surgical groups were identified: AVR for aortic regurgitation (n = 370); AVR for predominant aortic stenosis (n = 1,072); AVR for aortic stenosis (AS) with CABG (n = 914); and isolated CABG (n = 11,156). The complete fasting lipid profiles of patients were collected, analyzed by group, and compared. RESULTS: Analysis by Spearman's correlation showed that total cholesterol levels, triglycerides and low-density lipoproteins (LDL-C) were modestly, yet significantly, increased in each successive group, while high-density lipoproteins were decreased. AS patients undergoing isolated AVR had significantly higher total cholesterol (215 versus 201 mg/dl; p <0.0001), triglycerides (125 versus 104 mg/dl; p <0.0001) and LDL-C (139 versus 132 mg/dl; p = 0.003) than those undergoing AVR for aortic regurgitation. Total cholesterol >200 mg/dl was significantly associated with AS, even after adjusting for differences in age, sex, diabetes mellitus and hypertension, with an odds ratio of 1.5 (95% confidence interval, 1.2-2.0; p = 0.001). CONCLUSION: Progressively abnormal lipid profiles are associated with AS and coronary disease in patients undergoing AVR. This evidence helps to extend the link between dyslipidemia and AS in a large consecutive series of patients.

In utero hematopoietic stem cell transplantation: a caprine model for prenatal therapy in inherited metabolic diseases.

OBJECTIVES: We explored the feasibility and efficacy of in utero hematopoietic stem cell transplantation in the caprine animal model system with the objectives of determining procedures for transplantation and establishing methods for detecting engraftment. METHODS: Male fetal liver hematopoietic stem cells were injected into female fetuses during the immunotolerant period, using either hysterotomy or ultrasound-guided injections. RESULTS: The rate of fetal death was much lower for the ultrasound-guided injections. Donor cells were observed in the peritoneal fluid of 4 fetuses 3 days after injection, but no donor cells were detected in tissues at longer time periods. CONCLUSIONS: Ultrasound-guided injection of hematopoietic stem cells into the abdomen of a developing fetus is safe and feasible. The parameters required for successful engraftment have not yet been identified.