NONMEM法估算中国癫痫患者苯妥英的群体药动学参数

临床上常规收集的161例门诊癫痫患者苯妥英(DPH)的每日剂量—稳态血药浓度数据258对,应用NONMEM程序一步估算其群体药动学参数(meansand、variances),并定量地分析体重、性别、合并用药对最大消除速率V_m(mg·d^-1),年龄对米-曼氏常数Km(μg·ml^-1)的影响。异性间DPH的V_m无显著差异,群体特征病人(体重60kg,年龄≥15a,未合并用苯巴比妥、安定或硝基安定)的V_m为439mg·d^-1,K_m为6.21μg·ml^-1。体重对V_m的调整值为WT/60的0.57次方,合并用药时V_m增加8.4mg·d^-1,年龄<15a则K_m下降7%。     

Ontogeny of the cell outward dopamine transporter in canine renal tissues

Summary— The present work has determined the activities of aromatic L-amino acid decarboxylase (AAAD) and evaluated the presence of an active transport system for dopamine in renal tissues of developing dogs (newborn puppies less than 24 hours after birth, animals at the age of 10 days and 2 months) and adult animals. AAAD activity (V_max, in pmol/mg protein/h) as determined in kidney homogenates was found to be in the adult dog kidney (V_max = 3216 ± 268) higher (p < 0.05) than that occurring in the three other groups of animals; no significant difference on AAAD activity was observed between the 10 day-old (V_max = 1139 ± 185) and the 2 month-old dogs (V_max = 783 ± 23). AAAD activity in newborn puppies (V_max = 259 ± 40) was markedly lower than in the three other groups. A considerable amount of the total dopamine formed from added L-DOPA in kidney slices, depending on the age, was found to escape into the incubation medium. The application of the Michaelis-Menten equation to the net transport of newly-formed dopamine has allowed the identification of a saturable (carrier-mediated transfer) and a non-saturable component (diffusion). The V_max (nmol/g/15 min), K_m (μM) values for the saturable component and diffusion constant (μmol^?1) were as follows: adult (V_max = 112 ± 16; K_m = 319 ± 35; diffusion constant = 0.0009 ± 0.0001), 2 month-old (V_max = 19 ± 5; K_m = 48 ± 14; diffusion constant = 0.0007 ± 0.0002), 10 day-old (V_max = 25 ± 3; K_m = 69 ± 20; diffusion constant = 0.0033 ± 0.0007) and newborn (V_max = 6 ± 1; K_m = 16 ± 6; diffusion constant = 0.0095 ± 0.0010). In conclusion, renal AAAD develops with age, though some AAAD activity can already be detected at birth. The dopamine outward transporter appears to be considerably immature at birth, but undergoes rapid maturation within the next 10 days; however, development of AAAD and of the renal dopamine outward transporter still proceedes from the age of 2 months until adulthood.     

Low flow oxygen therapy in infants

Fifty one infants who were oxygen dependent after treatment for neonatal respiratory disease were entered into a study programme where 100% oxygen was delivered at low flow through a nasal catheter. Thirty five (69%) of the infants were discharged home and the remainder were either discharged to a convalescent hospital or back to their peripheral referring hospital. Excluding repeat admissions for monitoring or for the treatment of acute infections, 2760 hospital days (79 days/patient) were saved, representing a financial saving of $11990 (pounds 6500) per treated infant. A home low flow oxygen therapy programme has benefits to the infant/parent relationship, provides a more constant flow of oxygen than conventional methods, and the early hospital discharge represents a considerable financial saving.     

Monocyte-macrophage-derived acidic isoferritins: normal feedback regulators of granulocyte-macrophage progenitor cells in vitro

The recent identification of a leukemia-associated inhibitory activity (LIA) against granulocyte-macrophage progenitor cells (CFU-GM) as acidic isoferritins has now led to detection of this activity in normal bone marrow and blood cells. Detection of this activity depends on stimulation of CFU-GM by granulocyte-macrophage colony stimulatory factors (GM-CSF), and some conditioned media (CM) sources of GM-CSF (human placental and monocyte, mouse macrophage and WEHI-3) contained low levels of acidic isoferritin that lowered colony formation. Inactivation or removal of this activity increased the stimulatory capacity of the CM. CM depleted of acidic isoferritins or CM originally devoid of this activity (human GCT, 5637, Mo, lymphocytes: mouse L cells or pokeweed-mitogen-stimulated spleen cells) increased the sensitivity of the assay to detect acidic isoferritin inhibitory activity. This activity was selectively contained and released from normal monocytes and macrophages. Restriction of this activity to mononuclear phagocytes was substantiated, as only continuous cell lines of monocytes and macrophages or lines capable of induction to this lineage contained and released acidic isoferritin inhibitory activity. The cells of origin and target cells of action suggest that acidic isoferritin-inhibitory activity can be considered as a negative feedback regulator, at least in vitro.     

Do pediatricians manage influenza differently than internists?

Background  

Little is known about how pediatricians or internists manage influenza symptoms. Recent guidelines on antiviral prescribing by the Centers for Disease Control and Prevention (CDC) make almost no distinction between adults and children. Our objective was to describe how pediatricians in two large academic medical institutions manage influenza and compare them to internists.     

p16, p53, EGFR expression and KRAS mutation status in squamous cell cancers of the anus: Correlation with outcomes following chemo-radiotherapy

Background and Purpose

Squamous cell carcinomas of the anal canal are associated with infection with Human Papilloma Viruses (HPVs). Chemo-radiotherapy (CRT) gives 70% 3-year relapse-free survival. Improved predictive markers and therapeutic options are required.

Methods

Tumours from 153 patients treated with radical chemo-radiotherapy (50.4 Gy in 28# with concurrent Mitomycin and 5-Fluorouracil between 2004 and 2009) were retrieved and immunohistochemistry performed for p16^INK4A, p53 and EGFR and correlated with outcome. Primary and relapsed samples were analysed for mutations in KRAS.

Results

137/153 (89.5%) stained moderately or strongly for p16^INK4A. p16^INK4A correlated strongly with outcome. 37/137 patients demonstrating moderate/strong p16^INK4A expression relapsed (27.0%), as opposed to 10/16 (62.5%) with absent/weak staining (log rank test p < 0.001). p16 and p53 expression were inversely correlated. p16^INK4A negative tumours were more frequent in men. p16^INK4A negative patients had significantly worse overall survival (p < 0.001). No mutations in KRAS were identified in primary tumours or relapses following treatment.

Conclusions

p16^INK4A is strongly associated with relapse in SCC of the anus and identifies patients with very poor rates of relapse-free and overall survival. Primary and recurrent anal cancer expresses wild type KRAS, unaffected by treatment, supporting trials targeting EGFR in poor risk/recurrent anal cancer.     

Effects of acute treatment with a tryptophan-rich protein hydrolysate on plasma amino acids,mood and emotional functioning in older women

Rationale

Effective functioning of the neurotransmitter serotonin is important for optimal cognitive and emotional function. Dietary supplements able to increase availability to the brain of the precursor amino acid, tryptophan (TRP), and thereby enhance serotonin synthesis, can have measurable impact on these psychological processes.

Objectives

This study involves a randomised controlled trial of a TRP-rich egg-white protein hydrolysate (DSM Nutritional Products Ltd., Switzerland) on plasma amino acids, cognition, mood and emotional processing in older women.

Methods

Following a baseline test day without treatment, 60 healthy women aged 45–65 years received drinks containing either 2 or 4 g of TRP-rich protein hydrolysate product or 3.11 g casein hydrolysate as a control. One hour later, they undertook a 2-h battery of cognitive and emotional tests.

Results

The TRP-rich protein hydrolysate produced the expected dose-dependent increase in the ratio of plasma TRP to competing large neutral amino acids. TRP-rich protein hydrolysate (2 g only) prevented both the decline in wellbeing and increase in fatigue seen over the test session in the control group. This treatment dose resulted in a significant shift in emotional processing towards positive words and reduced negative bias in assessing negative facial expressions. Effects on cognition were small and not statistically reliable and are not reported here. However, there was no evidence for any adverse effects.

Conclusions

Consumption of a low dose of TRP-rich protein hydrolysate may have beneficial effects on emotional function that could promote feelings of wellbeing, possibly conferring resistance to deterioration in mood in healthy subjects or depressive episodes.     

Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding

A 63-year-old man was evaluated for a lifelong history of bleeding commencing with frequent epistaxis as a child; all previous routine coagulation parameters were within the normal range. The patient's hemorrhagic disorder is characterized predominantly by delayed bleeding at surgical sites. In the resting state, there was no clinical or laboratory evidence of excessive fibrin(ogen)olysis. Bleeding was not caused by disseminated intravascular coagulation, factor XIII deficiency, alpha 2-antiplasmin deficiency, or dysfibrinogenemia. It was found that the patient was deficient in plasma PAI-1 antigen and activity but with approximately half normal antigen and normal activity of platelet PAI-1. The low concentration of plasma PAI-1 was insufficient to neutralize circulating t-PA, resulting in high t-PA activity with normal antigen and causing the hyperfibrinolytic activity observed. Studies on seven family members of the proband indicated autosomal inheritance of plasma PAI-1 deficiency. Studies on this patient emphasize a clear correlation between decreased plasma PAI-1 activity and hyperfibrinolytic bleeding and also emphasize the unique role of plasma PAI-1 in the balance between the coagulation and fibrinolytic mechanisms.