Tissue distribution of amiodarone and desethylamiodarone in rats after multiple intraperitoneal administration of various amiodarone dosages

Tissue distribution of amiodarone (Cordarone) and desethylamiodarone in the rat was studied after repeated intraperitoneal administration of the drug. Tissue and serum concentrations of amiodarone and desethylamiodarone were determined by high-performance liquid chromatography. The levels of amiodarone and desethylamiodarone in serum and tissues obtained after repeated intraperitoneal application of doses varying from 25 mg to 200 mg/kg show that the accumulation of amiodarone and desethylamiodarone in the rat is dose-dependent and both drugs are preferentially distributed in decreasing order in adipose tissue, lung, liver, kidney and thyroid gland. The penetration of the drug and its metabolite into brain was poor and with all the applied dosages brain levels were considerably lower than the corresponding serum levels. Desethylamiodarone serum and tissue concentrations were substantially lower than the corresponding amiodarone concentrations and varied from 1 to 48% (mean 15%) depending on the dosage used and the kind of tissue. The amiodarone tissue/serum concentration ratios were exceptionally high in adipose tissue (1,000-4,000) and moderate to high in the other tissues except brain (5-90), and indicate an extensive distribution of the drug with fat as a reservoir with a large storage capacity. The levels of amiodarone and desethylamiodarone, obtained with 50 mg/kg and 100 mg/kg dosages, showed in function of time clearly an increase in serum and tissues. The observed amiodarone tissue/serum ratios in function of time revealed no further significant increase (p less than or equal to 0.05) after 3 injections over a 6-day period, indicating the attainment of "steady-state".(ABSTRACT TRUNCATED AT 250 WORDS)     

Patterns of contrast enhancement of benign and malignant hepatic neoplasms during bolus dynamic and delayed CT

Bolus dynamic and delayed computed tomographic (CT) scans of the liver were evaluated in 43 patients with 54 hepatic hemangiomas and 111 patients with primary or secondary malignant hepatic neoplasms. Twelve patterns of contrast enhancement were recognized during the bolus dynamic phase and delayed scanning. A "typical" CT pattern for hemangiomas (present in 29 of 54 hemangiomas [53.7%]) was established: (a) diminished attenuation prior to intravenous contrast medium administration (excluding lesions arising in a liver with diffuse fatty infiltration), (b) peripheral contrast enhancement during the bolus dynamic phase, and (c) complete isodense fill-in on delayed scan images. Using these criteria, we distinguished hemangiomas from malignant neoplasms in most patients. Only one of 63 (1.6%) malignant neoplasms manifested these typical CT criteria of hemangioma. There is an 86% chance that a lesion with the typical CT appearance of hemangioma is actually a hemangioma, even when found in a patient with a known nonhepatic primary neoplasm.     

平胃散对湿阻中焦模型大鼠血浆抗利尿激素及红细胞内钠、钾浓度的影响

目的:探索湿阻中焦证的病理机制,并探讨平胃散对湿阻中焦证的作用机理。方法:选用湿阻中焦证大鼠模型,给予平胃散配伍利水药,观测各组大鼠血浆抗利尿激素(ADH)的浓度及红细胞内电解质Na~+、K~+浓度。结果:湿阻造模组大鼠与正常组相比ADH显著升高(P<0.01);细胞内的Na~+增高,K~+显著降低(P<0.05)。给予平胃散后,高、中、低剂量组及加泽泻组大鼠ADH基本恢复正常;细胞内的Na~+下降至接近于正常,K~+尤明显变化;不造模给药组与正常组比较ADH显著升高(P<0.05),Na~+、K~+明显下降(P均<0.01)。结论:(1)血浆ADH浓度升高、细胞内Na~+增多、K~+降低在湿阻中焦证形成中起重要作用。(2)平胃散治疗湿阻中焦证的作用机理与调节ADH和细胞内Na~+、K~+浓度有关,且可能存在双向调节机制。     

Early stage nasopharyngeal carcinoma: radiotherapy dose and time factors in tumor control

OBJECTIVE: To evaluate radiotherapy dose and length of treatment in the control of early stage nasopharyngeal carcinoma (NPC) treated with a combination of external radiotherapy and brachytherapy, MATERIALS & METHODS: We reviewed the records of 133 patients with early stage nasopharyngeal carcinoma (stage I or II, AJC/UICC staging system) who received definitive radiotherapy in Chang Gung Memorial Hospital from 1979 to 1991. The median follow-up time was 7.1 years with a minimum of 2 years. All patients were treated with megavoltage external radiotherapy to the nasopharynx area (63-72 Gy) followed by high dose rate intracavitary brachytherapy (5-16.5 Gy in one to three fractions, spaced 1-2 weeks apart). The median total dose and time of irradiation was 75 Gy (69.8-81.4 Gy) and 11.6 weeks (7.8-20 weeks) respectively. Survival analysis was used to examine the effect of several variables on prognosis. RESULTS: The 5-year rates were 86.4% for local control, 84.7% for disease free survival, 88.5% for actuarial survival and 84.2% for overall survival. The treatment group (combination of time and dose of irradiation) was the most important prognostic factor according to Cox's proportional hazard model. Patients receiving radiation at a total dose of < or = 75 Gy completed in < 12 weeks showed the best prognosis. CONCLUSION: Treatment time and total treatment dose are both important factors in treating early stage NPC. Decreasing the total radiation time to < 12 weeks and not exceeding a radiation dose of 75 Gy gave the best results.      

Smoking and thyroid

Current smoking in population surveys is associated with a slight dose‐dependent fall of serum TSH, likely secondary to a rise of serum FT4 and FT3 induced by activation of the sympathetic nervous system; it is independent of iodine intake. In contrast, the slightly greater thyroid size in smokers is observed in iodine‐deficient but not in iodine‐sufficient areas and caused by competitive inhibition of thyroidal iodide uptake by thiocyanate. Smokers have an increased prevalence of nontoxic goitre and thyroid multinodularity, at least in iodine‐deficient areas. Current smoking reduces dose dependently the risk of thyroid cancer, which is more pronounced for papillary than for follicular types; the risk in former smokers approaches that of never smokers. The lower TSH and lower body mass index in smokers might contribute to this reduced risk. Current smoking lowers the risk of developing thyroid peroxidase and thyroglobulin antibodies and subclinical and overt autoimmune hypothyroidism; the effect is dose dependent, but disappears within 3 years after quitting smoking. There is evidence from an animal model of experimental autoimmune thyroiditis that anti‐inflammatory effects of nicotine are involved. In contrast, smoking is a dose‐dependent risk factor for Graves’ hyperthyroidism and especially for Graves’ ophthalmopathy. Smoking is related to a higher recurrence rate of Graves’ hyperthyroidism, a higher risk on Graves’ ophthalmopathy after 131I therapy and a less favourable outcome of GO treatment with steroids or retrobulbar irradiation. The observed associations with smoking likely indicate causal relationships in view of consistent associations across studies, the presence of dose–response effects and disappearance of associations after cessation of smoking.     

Acute exacerbation of chronic obstructive pulmonary disease: Influence of social factors in determining length of hospital stay and readmission rates

BACKGROUND:

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the leading reason for hospitalization in Canada and a significant financial burden on hospital resources. Identifying factors that influence the time a patient spends in the hospital and readmission rates will allow for better use of scarce hospital resources.

OBJECTIVES:

To determine the factors that influence length of stay (LOS) in the hospital and readmission for patients with AECOPD in an inner-city hospital.

METHODS:

Using the Providence Health Records, a retrospective review of patients admitted to St Paul’s Hospital (Vancouver, British Columbia) during the winter of 2006 to 2007 (six months) with a diagnosis of AECOPD, was conducted. Exacerbations were classified according to Anthonisen criteria to determine the severity of exacerbation on admission. Severity of COPD was scored using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. For comparative analysis, severity of disease (GOLD criteria), age, sex and smoking history were matched.

RESULTS:

Of 109 admissions reviewed, 66 were single admissions (61%) and 43 were readmissions (39%). The number of readmissions ranged from two to nine (mean of 3.3 readmissions). More than 85% of admissions had the severity of COPD equal to or greater than GOLD stage 3. The significant indicators for readmission were GOLD status (P<0.001), number of related comorbidities (OR 1.47, 95% CI 1.10 to 1.97; P<0.009) and marital status (single) (OR 4.18, 95% CI 1.03 to 17.02; P<0.046). The requirement for social work involvement during hospital admission was associated with a prolonged LOS (P<0.05).

CONCLUSIONS:

The results of the present study show that disease severity (GOLD status) and number of comorbidities are associated with readmission rates of patients with AECOPD. Interestingly, social factors such as marital status and the need for social work intervention are also linked to readmission rates and LOS, respectively, in patients with AECOPD.     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice

During illness, major changes in thyroid hormone metabolism and regulation occur; these are collectively known as non-thyroidal illness and are characterized by decreased serum triiodothyronine (T(3)) and thyroxine (T(4)) without an increase in serum TSH. Whether alterations in the central part of the hypothalamus-pituitary-thyroid (HPT) axis precede changes in peripheral thyroid hormone metabolism instead of vice versa, or occur simultaneously, is presently unknown. We therefore studied the time-course of changes in thyroid hormone metabolism in the HPT axis of mice during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS).LPS rapidly induced interleukin-1beta mRNA expression in the hypothalamus, pituitary, thyroid and liver. This was followed by almost simultaneous changes in the pituitary (decreased expression of thyroid receptor (TR)-beta2, TSHbeta and 5'-deiodinase (D1) mRNAs), the thyroid (decreased TSH receptor mRNA) and the liver (decreased TRbeta1 and D1 mRNA). In the hypothalamus, type 2 deiodinase mRNA expression was strongly increased whereas preproTRH mRNA expression did not change after LPS. Serum T(3) and T(4) fell only after 24 h.Our results suggested almost simultaneous involvement of the whole HPT axis in the downregulation of thyroid hormone metabolism during acute illness.     

Thyroid autoimmunity and miscarriage

To ascertain the strength of the association between thyroid autoimmunity and miscarriage, we performed a meta-analysis of both case-control and longitudinal studies performed since 1990 when this association was first described. A clear association between the presence of thyroid antibodies and miscarriage was found with an odds ratio (OR) of 2.73 (95 % confidence interval (CI), 2.20-3.40) in eight case-control and ten longitudinal (OR, 2.30; 95 % CI, 1.80-2.95) studies. This association may be explained by a heightened autoimmune state affecting the fetal allograft, of which thyroid antibodies are just a marker. Alternatively, the association can be partly explained by the slightly higher age of women with antibodies compared with those without (mean+/-S.D. age difference, 0.7+/-1.0 years; P<0.001). A third possibility is mild thyroid failure, as thyroid-stimulating hormone (TSH) levels in antibody-positive but euthyroid women are higher than in antibody-negative women: difference 0.81+/-0.58 mU/l (P=0.005). Randomized clinical trials with l-thyroxine (aiming at TSH values between 0.4 and 2.0 mU/l) and with selenium (to decrease antibodies against thyroid peroxidase) are clearly needed to elucidate further the nature of this association.