Tissue-specific expression of human lipoprotein lipase in the vascular system affects vascular reactivity in transgenic mice.

1. The role of smooth muscle-derived lipoprotein lipase (LPL) that translocates to the endothelium surface on vascular dysfunction during atherogenesis is unclear. Thus, the role of vascular LPL on blood vessel reactivity was assessed in transgenic mice that specifically express human LPL in the circulatory system. 2. Aortic free fatty acids (FFAs) were increased by 69% in the transgenic mice expressing human LPL in aortic smooth muscle cells (L2LPL) compared with their non-transgenic littermates (L2). 3. Contractility to KCl was increased by 33% in aortae of L2LPL mice. Maximal contraction to phenylephrine (PE) was comparable in L2 and L2LPL animals, while the frequency of tonus oscillation to PE increased by 104% in L2LPL mice. 4. In L2LPL animals, *NO mediated relaxation to acetylcholine (ACh) and ATP was reduced by 47 and 32%, respectively. In contrast, endothelium-independent relaxation to sodium nitroprusside (SNP) was not different in both groups tested. 5. ATP-initiated Ca(2+) elevation that triggers *NO formation was increased by 41% in single aortic endothelial cells freshly isolated from L2LPL animals. 6. In aortae from L2LPL mice an increased *O(2)(-) release occurred that was normalized by removing the endothelium and by the NAD(P)H oxidase inhibitor DPI and the PKC inhibitor GF109203X. 7. The reduced ACh-induced relaxation in L2LPL animals was normalized in the presence of SOD, indicating that the reduced relaxation is due, at least in part, to enhanced *NO scavenging by *O(2)(-). 8. These data suggest that despite normal lipoprotein levels increased LPL-mediated FFAs loading initiates vascular dysfunction via PKC-mediated activation of endothelial NAD(P)H oxidase. Thus, vascular LPL activity might represent a primary risk factor for atherosclerosis independently from cholesterol/LDL levels.     

In utero aminoglycosides-induced nephrotoxicity in rat neonates

Pregnant Wistar females were treated with gentamicin (G), netilmicin (N) or amikacin (A) during two periods of pregnancy covering organogenesis and the beginning of nephrogenesis. Deliveries occurred normally. We studied functional effects--influence of sex, litter size, diuresis, creatinine clearance, G-kidney concentration, and kidney morphological alterations--in rat neonates on day 1 of life. After G and N, the creatinine clearance of the neonates was decreased according to the dosage given to the mother. Whatever the aminoglycoside, kidneys presented proximal tubular alterations (close to those observed in adults) at protonic microscopy and, with electron microscopy, some modifications of distal tubules and of mature and immature glomeruli. It is concluded that the developing kidney can be altered after treating pregnant mothers with aminoglycosides. This model of in utero-induced nephrotoxicity is dose-dependent. Mature and/or immature structures could be affected. The toxicity of the investigated antibiotics could be asserted as G greater than or equal to N greater than A.     

Dietary assessment of a population of pregnant women in Sheffield, UK

The present study examined the dietary intakes of a population of pregnant women living in the North of England. The objectives of the paper were to assess and describe the dietary intakes of the population and relate the findings to existing data on the diet of pregnant and non-pregnant women in the UK. A total of 250 pregnant women attending their first antenatal appointment at the Jessop Wing Hospital, Sheffield, UK were recruited. Information on their diet was assessed by an interviewer-administered semi-quantified food frequency questionnaire (FFQ). The mean intakes as assessed by the FFQ were similar to other studies of UK pregnant population; however Sheffield pregnant women had lower intakes of calcium and folate. Study findings were also related to the National Diet and Nutrition Survey and to the Estimated Nutrient Intakes (EAR). Of the study participants, 40 % did not meet the EAR for calcium, 67 % for iron and 69 % for folate. Subgroup comparisons suggested lower nutrient intakes of participants living in the 40 % most deprived electoral wards. The study findings suggest that the diet of pregnant women in Sheffield is characterised by low intakes of important nutrients for pregnancy such as folate and nutrient variations by electoral wards.     

A sheep model for thoracic aortic surgery in the presence of systemic coagulopathy.

Surgical repair of aneurysms, traumatic injuries, or congenital anomalies of the thoracic aorta are associated with high morbidity and mortality mainly as a result of excessive and uncontrollable hemorrhage from diffuse coagulopathy. We developed a model in sheep that simulates this coagulopathic state for experimentation with thoracic aorta surgery. This experimental animal model involves administering a 600-mg aspirin suppository once a day for the 2 days preceding surgery and a final dose on-call to surgery. Prior to cross-clamping the aorta, an intravenous (i.v.) bolus of heparin (400 IU/kg) was administered. Thirty minutes later, the i.v. heparin bolus was repeated. Pre- and intraoperative activated clotting time was 101 +/- 10 s and >1500 s (p < .0001); prothrombin time, 21 +/- 1 s and >100 s (p < .0001); and activated partial thromboplastin time, 20 +/- 1 s and >50 s (p < .0001), respectively. We utilized a partial cross-clamp-and-sew technique to anastomose a woven, gelatin-impregnated, 16-mm tube graft end-to-side to the descending thoracic aorta. Mean total blood loss was 1367 +/- 282 mL, which included mean blood loss from time of release of aortic cross-clamp to close (422 +/- 135 mL) and mean total blood output from chest tube drain (945 +/- 203 mL). The mean time to achieve hemostasis at suture lines after aortic cross-clamp release was 15.5 +/- 6.6 min. In conclusion, a sheep model with induced coagulation defects was successfully developed and reproducible for experimentation involving thoracic aortic surgery.     

Targeted therapies in interstitial lung disease secondary to systemic autoimmune rheumatic disease. Current status and future development

Autoimmune rheumatic diseases (ARD) are characterized by systemic manifestations and multiple organ involvement, including the lung. Interstitial Lung Disease (ILD) is a cardinal manifestation of lung involvement in patients with ARD and is associated with significant morbidity and mortality. Corticosteroids and immunosuppressive drugs are used as first –line treatment. Targeted therapies, such as biological disease modifying antirheumatic drugs (DMARDS) and anti- fibrotic agents are new treatment options. In this review we discuss the role of targeted therapies in patients with ILD secondary to ARD.     

Genotyping and antifungal susceptibility testing of Cryptococcus neoformans isolates from Cameroonian HIV-positive adult patients

Cryptococcus neoformans is the most common cause of meningitis amongst adult Africans with HIV/AIDS. The widespread use of fluconazole may lead to the emergence of isolates with reduced susceptibility. We studied C. neoformans isolates from HIV-infected patients with cryptococcal meningitis. Genotyping and antifungal testing were performed to assess the genetic diversity, occurrence of mixed infections and in vitro activity of antifungal agents. Isolates were recovered from cerebrospinal fluid prior to systemic antifungal treatment. Six isolates were studied for each sample (a total of 114 isolates from 19 patients). Serotyping was performed via LAC 1 and CAP 64 gene amplification and genotyping was performed using phage M13 core, (GACA)₄ and (GTG)₅ primers and restriction polymorphism analysis of the URA5 gene. Susceptibilities for amphotericin B, flucytosine, fluconazole, voriconazole and posaconazole were tested by the Sensititre YeastOne® method. All strains were identified as C. neoformans var. grubii serotype A. We identified nine major genotypes. Up to two genotypes were identified in the same sample. None of the isolates were resistant to the studied drugs. However, 13 of 114 strains exhibited a reduced susceptibility to fluconazole and 13 of 114 strains exhibited a reduced susceptibility to flucytosine. No correlation was found between the genotype and susceptibility. This study confirms the prevalence of C. neoformans serotype A in Cameroon. Two genotypes may be responsible for a single episode of cryptococcosis. The possibility of mixed infection and diminished susceptibility to fluconazole or flucytosine must be considered for the management of cryptococcosis.