Benefits and risks of simvastatin in patients with familial hypercholesterolaemia.

Familial hypercholesterolaemia is a frequent, inherited, monogenic disorder, associated with accelerated development of atherosclerotic disease leading to coronary artery disease. Life expectancy of patients with familial hypercholesterolaemia is reduced by 15-30 years unless they are adequately treated with lipid-lowering therapy. Given the chronic nature of this disease, the selection of a therapeutic approach should be strongly based on its long-term safety and tolerability. The introduction of HMG-CoA reductase inhibitors has revolutionised the treatment of familial hypercholesterolaemia.Simvastatin 40-80 mg/day effectively reduces serum low density lipoprotein (LDL)-cholesterol levels. Furthermore, simvastatin reduces triglycerides and mildly raises high density lipoprotein-cholesterol levels. In addition to the hypolipidaemic effect, other potentially important effects, such as improvement of endothelial function and reduction of LDL oxidation and vascular inflammation, have been associated with HMG-CoA reductase inhibitor therapy. Simvastatin has also been shown to abolish the progression, and even facilitate the regression, of existing human atherosclerotic lesions.The good safety and tolerability profile of simvastatin is clearly highlighted by the low rate of therapy discontinuation observed in several population-based clinical trials. The most common adverse events leading to the discontinuation of therapy are gastrointestinal upset and headache. Asymptomatic elevations in liver transaminase levels and myopathy are uncommon.The overwhelming clinical evidence regarding the long-term use of HMG-CoA reductase inhibitor therapy in patients with familial hypercholesterolaemia together with the long-term safety data (particularly relating to simvastatin) provide support for the use of this drug as a first-line agent when pharmacological treatment is indicated. Early intervention with simvastatin treatment can be successfully implemented with favourable economic benefits.     

CD24 expression on human keratinocytes

Abstract: CD24 or Nectadrin is a cell surface glycoprotein expressed in pre-B lymphocytes, T lymphocytes, neurons, muscle cells and carcinoma cells. Its function is not completely known, but it has been suggested that it is involved in cell adhesion and signalling. CD24 has recently been identified as the human molecule homologous to the murine heat-stable antigen (HSA). HSA is expressed by murine keratinocytes and delivers costimulatory signals in T-cell activation. Long-term cultures of normal human keratinocytes (HKC) were obtained from skin of human female breast sections and either left untreated or were treated with phorbol-12-myristate-13-acetate (PMA) at 10–100 ng/ml, calcium 0.5–2 mM or IFN-γ 100–1000 U/ml, for 24–48 h. Using RT-PCR and flow cytometry we showed that HKC express low levels of CD24 even under basal conditions, and the treatment with calcium, PMA or IFN-γ increased levels of CD24 mRNA and protein. To the best of our knowledge, this is the first report to measure CD24 expression and production by cultured HKC in basal conditions and after stimulation. Further studies are needed to determine biological and therapeutical relevance of these findings.     

MR susceptometry: an external-phantom method for measuring bulk susceptibility from field-echo phase reconstruction maps

A novel method for estimating the susceptibility of an object by using the magnetic resonance (MR) imaging field distortions in an external-reference water bath next to the object is described. The field measurement was obtained with a phase reconstruction from a gradient-echo acquisition. A field model of an arbitrary object in a static magnetic field was discretely calculated from geometry determined from the magnitude reconstruction. Least-squares estimation yields the susceptibility of the object. Required (and proven) assumptions include validity of superposition, object homogeneity, negligible higher-order field terms, field-model accuracy, geometric-model accuracy, and correlation of gradient-echo phase to field distortion. MR susceptometry estimation of phantoms yielded susceptibility estimates that correlated well with known values (r >.9975). This MR susceptometry method is a first step toward quantitation of iron levels through MR imaging phase information in patients with iron overload.     

Role of glutamate in the amygdala and lateral hypothalamus in conditioned taste aversion

The role of glutamate in conditioned taste aversion was investigated. Both, in the amygdala (AMYG) and in the lateral hypothalamus (LH) extracellular levels of glutamate were assessed by microdialysis and capillary electrophoresis with laser induced fluorescence detection. Rats were conditioned by pairing a novel flavor (strawberry flavor) with an intraperitoneal injection of lithium chloride. When the conditioned stimulus (strawberry flavored solution) was injected into the mouth of conditioned rats, there was an increase of glutamate release in the AMYG, and a decrease in glutamate release in the LH. These results predicted that glutamate release in the AMYG and the LH was involved in CTA. This possibility was tested by MK-801 (glutamate antagonist) and glutamate microinjections. MK-801 injections in AMYG attenuated the rejection of the novel flavor, and in the LH did not cause any effect on CTA. Glutamate microinjections in the AMYG caused CTA. These results suggest that glutamatergic activity in the AMYG might be a relevant neurochemical correlate and cause of conditioned taste aversion.     

The effect of isoflurane 0.6% on respiratory mechanics in anesthetized-paralyzed humans is not increased at concentrations of 0.9% and 1.2%

PURPOSE: To assess the dose-dependent effect of low concentrations of isoflurane on respiratory mechanics in normal subjects. METHODS: We studied 12 non-premedicated ASA I patients scheduled for lower abdominal or extremity surgery. After thiopental 5-7 mg*kg(-1) iv and succinylcholine 1 mg x kg(-1) iv, the trachea was intubated and an esophageal balloon was placed optimally by the occlusion test. After introduction of N(2)O and muscle paralysis with vecuronium, we studied 0, 0.6, 0.9 and 1.2% isoflurane. We recorded flow (F), airway opening and esophageal pressures. Signals were amplified, filtered, sampled at 100 Hz, and then fed in a 12-bit analogue-digital converter in a personal computer. Data were collected and analyzed using LABDAT and ANADAT software. Signals were acquired for 60-90 sec during mechanical ventilation (10 mL x kg(-1), 10 breaths x min(-1), I:E ratio 1:2). We estimated respiratory system (RS), lung (L) and chest wall (W) dynamic elastance (E) and resistance (R) by P(t) = EV(T)(t) + RF(t) + K, where t is time, V(T) tidal volume from integration of F, and K an estimation of end-expiratory pressure. ANOVA was used for comparing the basal state with the three concentrations. RESULTS: E and R were statistically lower at 0.6, 0.9 and 1.2% compared to basal values for RS, L and W. Concentrations equal to or higher than 0.6% did not further change respiratory mechanics, except for E(L1.2) compared to E(L0.6,) 12.37 +/- 5.72 and 13.52 +/- 5.64 cm H(2)O.L(-1), respectively. CONCLUSION: Isoflurane concentrations between 0.6-1.2% are not associated to a dose-dependent effect on respiratory mechanics.     

Histoclinical basis for a new classification of hemorrhoidal disease

The present classification of first, second, and third grade hemorrhoids only reflects variation in size of a normal human tissue and does not relate to "hemorrhoidal disease." Cross-sections and coronal sections of the anal canal in 32 fetuses, with ages ranging from 28 to 38 weeks of development, were studied and the following fundamental facts were found: in the lumen of the anal canals of fetuses, there are prominences of mucosa formed by conjunctive and muscular tissue, arterial and venous vessels and glands, arranged without following any particular pattern, which resemble similar formations found in the adult that protrude equally in the inside of the canal, known as hemorrhoids. The muscular tissue, smooth or striated, is grouped in bundles, and bunches of collagen fibers of homogeneous, nonfragmented, and regular aspect are found between them. Blood vessels have an ample lumen with a defined structure of collagen tissue as well as muscular tissue in its walls. Prominences of mucosa are connected to the remainder of the intestinal wall by defined conjunctive thick, nonfragmented fibers, that permit firm adherence. In healthy adults, the findings were similar but there was an evident degenerative process in the collagen fibers. In 100 surgical specimens of hemorrhoidectomies, the histologic investigation demonstrated a severe inflammatory reaction that especially affected the blood vessel wall and conjunctive tissue, which probably produced an ischemic lesion of the mucosa that could condition the onset of a vascular thrombosis, allowing displacement of the mucosa and its protrusion through the anus. The files of 815 patients suffering from hemorrhoidal disease were also studied. The main physical findings were bleeding, thrombosis of the internal hemorrhoidal plexus, prolapse of the anal cushions, or a combination of these. The authors propose to classify hemorrhoidal disease as bleeding, prolapsing, thrombotic, and mixed hemorrhoidal disease, aiming toward a rational treatment.     

Production of specific retinal S antigen antibodies in patients with retinal detachment

One hundred patients with retinal detachment (61 primary operations and 39 reoperations) were studied for titers of autoantibodies to human retinal S antigen using the enzyme-linked immunosorbent assay technique (ELISA). There was no statistically significant difference when comparing the group of patients with primary retinal detachment with the control group. However, a statistically significant increase in anti-S titers was recorded when a comparison was made between the group of reoperated patients and the control group (²,P < 0.001) and between the group of reoperated subjects and the group of patients operated on for the first time (²,P < 0.005).Presented at the XVth Meeting of the Club Jules Gonin, Copenhagen, 10–15 August 1986     

A severe form of amyloidotic polyneuropathy in a Costa Rican family with a rare transthyretin mutation (Glu54Lys)

Four affected siblings in a Costa Rican family presented an aggressive polyneuropathy with widespread involvement of many visceral organs and onset during the third decade of life with rapid loss of muscle mass in the lower limbs and severe dysautonomy. The medical histories include vitreous opacity, cardiac enlargement, dermal and gastrointestinal infiltration, and autonomic dysfunction including circulatory compromise and gastrointestinal disturbances. Histological studies using Congo red stain and immunohistochemical assays with antibodies against the transthyretin (TTR) protein showed widespread deposition of amyloid in extracellular areas, including dermis and gastrointestinal lamina propia, endo- and perineural spaces, and vascular walls. A mutation search in the transthyretin (ttr) gene was performed seeking the cause of this severe form of familial amyloidotic polyneuropathy (FAP). We applied single-stranded conformational polymorphism (SSCP)-analyses followed by sequencing of the four exons of the ttr gene, revealing a point mutation in exon 3, a G to A transition that causes a Glu54Lys codon change. Western blots of plasma proteins incubated with anti-transthyretin antibodies after gel electrophoresis provided separation of wild-type and mutant TTR protein in affected family members.     

PTOV-1, a novel protein overexpressed in prostate cancer,shuttles between the cytoplasm and the nucleus and promotes entry into the S phase of the cell division cycle

PTOV1 was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer. The PTOV1 protein consists of two novel protein domains arranged in tandem, without significant similarities to known protein motifs. By immunohistochemical analysis, we have found that PTOV1 is overexpressed in 71% of 38 prostate carcinomas and in 80% of samples with prostate intraepithelial neoplasia. High levels of PTOV1 in tumors correlated significantly with proliferative index, as assessed by Ki67 immunoreactivity, and associated with a nuclear localization of the protein, suggesting a functional relationship between PTOV1 overexpression, proliferative status, and nuclear localization. In quiescent cultured prostate tumor cells, PTOV1 localized to the cytoplasm, being excluded from nuclei. After serum stimulation, PTOV1 partially translocated to the nucleus at the beginning of the S phase. At the end of mitosis, PTOV1 exited the nucleus. Transient transfection of chimeric green fluorescent protein-PTOV1 forced the entry of cells into the S phase of the cell cycle, as shown by double fluorescent imaging for green fluorescent protein and for Ki67, and also by flow cytometry. This was accompanied by greatly increased levels of cyclin D1 protein in the transfected cells. These observations suggest that overexpression of PTOV1 can contribute to the proliferative status of prostate tumor cells and thus to their biological behavior.