Design of clinical trials for chronic diseases: implications for periodontal disease

In order to make effective use of the statistical theory of design of clinical trials for chronic diseases such as periodontal disease, certain issues must be considered. Any clinical trial requires that the disease definition be well-specified; that patient eligibility be explicit; that the observation times be explicit; that the duration and endpoint of therapy be specified; that the duration of subsequent followup observation be specified; and that the unit of observation (e.g., tooth, set of teeth, patient) be defined. In a chronic disease, the potential biases that can readily be introduced by self-selection of patients who enter the trial and/or who return for subsequent observation become more important, because subjects are required to remain on treatment and/or observation for prolonged periods. Further, the cyclical nature of some chronic diseases may require special attention to baseline definitions of active disease and disease outcome. These issues are illustrated with examples from clinical trials of hypertension, breast cancer screening, and Polycythemia Vera. Implications for periodontal disease are discussed.     

多种血管新生指标在肝细胞肝癌中的表达及敏感性比较

目的　探讨血管新生指标CD34、CD31、vWF、Ⅳ型胶原纤维及层粘连蛋白在肝细胞肝癌(HCC)中的表达及意义 ,同时比较上述几种血管新生因子与增殖细胞核抗原 (PCNA)、病理指标及预后的相关性 ,以便筛选出有效的临床预后指标。方法　采用免疫组化方法 ,对 5 3例肝细胞肝癌的标本进行CD31、CD34、vWF、Ⅳ型胶原纤维及层粘连蛋白的染色、计数 ,并用检测数据与患者的临床资料进行统计分析。结果　统计染色的血管面积后发现 ,CD34与多种临床病理指标无相关性 ;CD31与肝内门静脉浸润相关 ;vWF与肿瘤的TNM分期及肝内门静脉浸润呈正相关 ;CollⅣ与肝内门静脉浸润呈正相关、与术后生存期呈负相关 ;Lam与肝硬化及术中出血量呈负相关、与术后生存期呈正相关。PCNA与肿瘤TNM分期有关。结论　在HCC中 ,CollⅣ、vWF、及CD31为肝细胞肝癌的有效血管新生及预后指标 ;Lam则与肝硬化及术中出血相关 ;PCNA指数肿瘤分期有关 ;CD34不能用作血管新生或预后指标     

THE PITUITARY-LEYDIG CELL AXIS IN MEN WITH SEVERE DAMAGE TO THE GERMINAL EPITHELIUM

Eighteen men (mean age 27, range 18-30 years) treated for Hodgkin's disease with 6-8 courses of MVPP (Mustine, Vinblastine, Procarbazine and Prednisolone) have had Leydig cell function assessed by their steroidogenic responses to stimulation by a single bolus dose of HCG (1000 units intramuscularly). Normal age-matched men (n = 16) acted as controls. Baseline immunoreactive FSH was markedly raised in the patients (mean 18.1 +/- SD 6.9 vs 2.0 +/- 1.5 IU/l, P less than 0.0001) reflecting damage to the germinal epithelium. Immunoreactive LH was also greater in patients (10.3 +/- 3.9 IU/l) than in controls (3.9 +/- 1.9 IU/l, P less than 0.0001). There were no differences between the baseline testosterone, androstenedione, oestradiol, oestrone and sex hormone binding globulin (SHBG) concentrations. The testosterone/SHBG ratios were similar in the two groups and there was no correlation between baseline LH and testosterone concentrations or testosterone/SHBG ratios. Testosterone, androstenedione, oestradiol and oestrone secretion in response to HCG stimulation were similar at 24 h and 96 h in both groups. In order to explain the paradox of elevated immunoreactive LH in the face of normal testicular steroidogenesis in such patients, LH biological activity (B) as well as LH immunoreactivity (I) and FSH and testosterone were estimated in a second similar group of patients (n = 17, mean age 27, range 17-43 years) and in a further age-matched control group (n = 17). Bioactive and immunoreactive LH levels were significantly increased (P less than 0.005 and P less than 0.001, respectively) in the patient group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Membrane flow within the myelin sheath in IDPN neuropathy

This report describes some aspects of beta,beta'-iminodipropionitrile (IDPN) neuropathy in rats as observed by ultrastructural methods and X-ray diffraction. Light microscopy shows gross swelling of the axons in proximal lumbar spinal roots 8 days after intraperitoneal injection of IDPN. Mean axon cross-sectional area and mean axon perimeter increased to 280% and 160% of their control values, respectively. At the same time, myelin membrane packing was not visibly disturbed. In addition, X-ray diffraction patterns, recorded under physiological conditions, demonstrate that the myelin lipid bilayer thickness and widths of the aqueous spaces between bilayers did not change. Related observations are made on posterior tibial nerve (PNS myelin) and ventral spinal cord (CNS myelin). The various observations together are interpreted in terms of a fluid myelin membrane. It is proposed that the myelin membrane flows during axon swelling even though normal membrane-membrane contacts are maintained within the sheath. Membrane flow and slippage between membranes are explained in terms of a molecular model of the myelin multilayer.     

Concentration and distribution pattern of selected micronutrients in preterm and term milk from urban Brazilian mothers during early lactation

The purpose of this study was to assess the concentration and binding pattern of zinc, iron, folate and vitamin B12 in milk of Brazilian women of low socioeconomic status giving birth at term or preterm, during early lactation. Protein, fat, total solids and ash concentrations were also determined. Protein and zinc concentrations decreased significantly as lactation proceeded whereas milk fat and folate increased with the lactation period. Total solids, ash, iron and vitamin B12 remained unchanged. Zinc was present mainly in the whey fraction while less than half of the total iron was present in this fraction, with no significant change due to stage of lactation. Unsaturated folate and vitamin B12 binding capacities and percentage of saturation of the folate binding protein increased with the stage of lactation. The vitamin B12 binding protein was highly unsaturated in all samples. There was no significant difference between term and preterm samples in the parameters investigated. Correlation analysis between milk components indicated significant relationships between total solids and fat, total zinc and whey zinc, folate and total folate binding capacity, unsaturated and total folate binding capacity, and unsaturated and total B12 binding capacity. In general, the nutrient concentrations found in this study are in good agreement with published data on milk composition of women from developed countries, with the possible exceptions of folate, which was lower, and iron, which was higher. The correlation of folate concentration with its binding protein found in this work supports the hypothesis of a regulatory role for folate levels in milk exerted by the folate binding protein in the mammary gland.     

Closed suction wound drainage and lower-segment caesarean section

Summary. In a randomized controlled study of wound suction drainage after transverse suprapubic incision for lower-segment caesarean section no significant advantages could be demonstrated for routine drainage in terms of wound infection, haematoma formation, duration of hospital stay or analgesic requirements.     

Ineffective hematopoiesis in folate-deficient mice.

A folate-free amino acid-based diet provided an opportunity to characterize the effects of folate depletion on growth, tissue folate levels, and hematopoiesis of mice under well-standardized conditions. Weanling mice were fed a folate-free, amino acid-based diet supplemented with either 0 or 2 mg folic acid/kg diet for 35 to 48 days. Folate concentrations were decreased in liver, kidney, serum, and erythrocytes in mice fed the folate-free diet. The folate-deficient mice had anemia, reticulocytopenia, thrombocytopenia, and leukopenia, all of which reverted to normal after folic acid was reintroduced to the diet. Hematopoietic organs of folate-deficient mice had alterations that were similar to those seen in folate-deficient humans except that in mice, the hyperplasia of hematopoietic tissue occurred in the spleen rather than in the marrow. Ferrokinetic studies showed a normal 59Fe-transferrin half-life, but the percentage of 59Fe-incorporation into red blood cells at 48 hours was markedly subnormal. The number of committed hematopoietic progenitors at the stages of erythroid colony-forming units (CFUs), megakaryocyte CFUs, and granulocyte-macrophage CFUs were all increased in folate-deficient mice. However, the progeny of these progenitors was markedly decreased in folate-deficient mice. Thus, the folate-deficient mice had "ineffective hematopoiesis" leading to pancytopenia, and they therefore provide a murine model of megaloblastic anemia.     

Linkage and association of adrenergic and dopamine receptor genes in the distal portion of the long arm of chromosome 5 with systolic blood pressure variation

Elevated blood pressure is an important risk factor for renal-, cerebro- and cardiovascular diseases. We used an efficient discordant sib-pair ascertainment scheme to investigate the impact of the distal end of the long arm of human chromosome 5 (chromosomal region 5q31.1-qter) containing genes for the alpha1B and beta2 adrenergic receptors and the dopamine receptor type 1A on variation of systolic blood pressure in young Caucasians. We measured eight highly polymorphic markers spanning this positional candidate gene-rich region in 427 individuals from 55 three-generation pedigrees containing 69 discordant sibling pairs, and calculated multipoint identity by descent (MIBD) probabilities. The results of genetic linkage and association tests indicate that the region between markers D5S2093 and D5S462 is significantly linked to one or more polymorphic genes influencing interindividual variation in systolic blood pressure levels. Since the alpha1B adrenergic receptor and dopamine receptor type 1A genes are located close to these markers, these data suggest that genetic variation in one or both of these G protein-coupled receptors, which participate in the control of vascular tone, plays an important role in influencing interindividual variation in systolic blood pressure levels.      

CAMPATH-1H IN RHEUMATOID ARTHRITIS--AN INTRAVENOUS DOSE-RANGING STUDY

Forty-one patients with active and refractory rheumatoid arthritis(RA) received a total of 100, 250 or 400 mg of CAMPATH-1H (CAMPATHis a trademark of Glaxo-Wellcome group companies, registeredin the US Patent and Trademark Office) over 5 or 10 days inan open, uncontrolled study. Following therapy, patients weremonitored for adverse effects and disease activity for 6 months.Therapy was associated with prolonged peripheral blood lymphopeniain all dosing cohorts. During the month immediately followingtherapy, lymphopenia was most profound in the 400 mg cohorts.The first dose of monoclonal antibody (Mab) was associated witha ‘flu’-like syndrome, more pronounced at higherinitial doses. One patient developed haemolytic-uraemic syndrome.There were a number of dose-related infections during the earlypost-treatment period and one fatal opportunistic infectionwhich followed additional immunosuppressive therapy. Antiglobulinresponses developed in 9 of 31 patients tested. The majorityof patients showed symptomatic improvement following therapyand 20% of patients maintained a 50% Paulus response at 6 months,all of whom were in the 250 or 400 mg cohorts. CAMPATH- 1H appearsto be an effective treatment for RA. Allowing for the smallnumber of patients treated, infections were more common withhigher doses, although this was not true for adverse eventsoverall, and therapeutic responses were more sustained at higherdosing levels. The broad specificity of CAMPATH- 1H may be appropriatefor the immunotherapy of RA and future studies should aim todefine a dose with an optimal therapeutic ratio. KEY WORDS: CAMPATH-1H, Rheumatoid arthritis, Immunotherapy, Monoclonal antibody, Antiglobulin response