Potentiation of central effects of L-dopa by an inhibitor of catechol-O-methyltransferase

Summary The effects of a COMT-inhibitor, U-0521, and a MAO-B-inhibitor, l-deprenyl, on L-dopa-induced circling behaviour were compared in 6-OHDA-lesioned rats. The actions of U-0521 and l-deprenyl on the anticataleptic effect of L-dopa were also studied. Both U-0521 and l-deprenyl were found to potentiate L-dopa-induced circling behaviour and anticataleptic effect of L-dopa. In both test systems the L-dopa potentiation of l-deprenyl was longer-lasting than that caused by U-0521. Thus inhibition of COMT, like inhibition of MAO, is able to enhance the central effects of L-dopa. This principle might be beneficial in the treatment of Parkinson's disease especially if COMT-inhibitors with greater performance can be developed.     

Ocular pharmacokinetic models of clonidine-3H hydrochloride

A single topical instillation of clonidine-³H HCl solution (0.2%) was administered to the rabbit eye (30 μl) in order to study the drug's ocular pharmacokinetics. Seven different tissues and plasma were excised and assayed for drug over 180min. By 45–60 min pseudoequilibrium is reached for the cornea, iris/ciliary body, and aqueous humor. Thereafter, drug levels in these tissues decline in parallel. The data are fit separately to a physiological model and a classical diffusion model for which seven ocular tissue compartments and a plasma reservoir are constructed for each model. Clearance terms and distribution equilibrium coefficients are determined from the tissue level data and used as parameters in fitting the mass balance differential equations representing the physiological model. The model parameters can also be fit to a 0.4% single dose. In a separate experiment, a topical infusion technique was designed to provide a constant rate input to the cornea until an apparent steady state was reached in aqueous humor at 55 min. Aqueous humor levels were assayed for clonidine over the infusion and postinfusion periods. The physiological model parameters are fit to the topical infusion data and show good agreement between the predicted and experimental data. The classical model is too complex to fit the data to integrated exponential equations primarily because the method of residuals is inadequate in determining a sufficient set of initial estimates. This is overcome by dividing the eight-compartment model into seven fragmental models, each representing one to five compartments. A stepwise procedure is developed in which initial estimates are obtained for each separate fragmental model and refined. The refined parameter values can then be used as initial estimates for the complex model. Differential equations for the complex model are fit simultaneously to tissue levels representing each compartment. By observation, the classical model fit the data more closely than the physiological model. Statistical moment theory is also applied to the topical infusion data to determine ocular pharmacokinetic parameters for clonidine. The calculated values are: corneal absorption rate constantk _a , 0.00139 min^?1; aqueous humor elimination rate constantk ₁₀ , 0.0658min^?1; mean residence timeMRT _d , 35.6 min; apparent steadystate volume of distributionV _ss, 0.530 ml; and ocular clearanceQ _e , 14.9 =μl/min. The fraction absorbed from the single instillation is estimated as 0.0163.     

Hepatic elimination of drugs with concentration-dependent serum protein binding

For a drug with concentration-dependent serum protein binding, the unbound fraction of drug decreases during the drug elimination process. The clearance of the drug at a given blood flow rate is lower than would be expected from the observed unbound fraction in venous blood from a noneliminating organ. Based on both the well-stirred and parallel tube models, simulations demonstrated that consideration of concentration-dependent binding during drug elimination is important when the intrinsic clearance is higher than the blood flow and when the unbound drug concentration is much greater than the dissociation equilibrium constant of the binding complex.Supported in part by Grant GM 28423 from the National Institutes of General Medical Sciences, NIH.     

Bayesian semiparametric joint modeling of longitudinal explanatory variables of mixed types and a binary outcome

Many prospective biomedical studies collect longitudinal clinical and lifestyle data that are both continuous and discrete. In some studies, there is interest in the association between a binary outcome and the values of these longitudinal measurements at a specific time point. A common problem in these studies is inconsistency in timing of measurements and missing follow-ups which can lead to few measurements at the time of interest. Some methods have been developed to address this problem, but are only applicable to continuous measurements. To address this limitation, we propose a new class of joint models for a binary outcome and longitudinal explanatory variables of mixed types. The longitudinal model uses a latent normal random variable construction with regression splines to model time-dependent trends in mean with a Dirichlet Process prior assigned to random effects to relax distribution assumptions. We also standardize timing of the explanatory variables by relating the binary outcome to imputed longitudinal values at a set time point. The proposed model is evaluated through simulation studies and applied to data from a cancer survivor study of participants in the Women's Health Initiative.     

Bone Marrow Adipocytes—Role in Physiology and Various Nutritional Conditions in Human and Animal Models

In recent years, adipose tissue has attracted a lot of attention. It is not only an energy reservoir but also plays important immune, paracrine and endocrine roles. BMAT (bone marrow adipose tissue) is a heterogeneous tissue, found mostly in the medullary canal of the long bones (tibia, femur and humerus), in the vertebrae and iliac crest. Adipogenesis in bone marrow cavities is a consequence of ageing or may accompany pathologies like diabetes mellitus type 1 (T1DM), T2DM, anorexia nervosa, oestrogen and growth hormone deficiencies or impaired haematopoiesis and osteoporosis. This paper focuses on studies concerning BMAT and its physiology in dietary interventions, like obesity in humans and high fat diet in rodent studies; and opposite: anorexia nervosa and calorie restriction in animal models.     

Recency-Weighted Statistical Modeling Approach to Attribute Illnesses Caused by 4 Pathogens to Food Sources Using Outbreak Data,United States

Foodborne illness source attribution is foundational to a risk-based food safety system. We describe a method for attributing US foodborne illnesses caused by nontyphoidal Salmonella enterica, Escherichia coli O157, Listeria monocytogenes, and Campylobacter to 17 food categories using statistical modeling of outbreak data. This method adjusts for epidemiologic factors associated with outbreak size, down-weights older outbreaks, and estimates credibility intervals. On the basis of 952 reported outbreaks and 32,802 illnesses during 1998–2012, we attribute 77% of foodborne Salmonella illnesses to 7 food categories (seeded vegetables, eggs, chicken, other produce, pork, beef, and fruits), 82% of E. coli O157 illnesses to beef and vegetable row crops, 81% of L. monocytogenes illnesses to fruits and dairy, and 74% of Campylobacter illnesses to dairy and chicken. However, because Campylobacter outbreaks probably overrepresent dairy as a source of nonoutbreak campylobacteriosis, we caution against using these Campylobacter attribution estimates without further adjustment.     

SARS-CoV-2 Serial Interval Variation,Montana, USA,March 1–July 31, 2020

We report mean severe acute respiratory syndrome coronavirus 2 serial intervals for Montana, USA, from 583 transmission pairs; infectors’ symptom onset dates occurred during March 1–July 31, 2020. Our estimate was 5.68 (95% CI 5.27–6.08) days, SD 4.77 (95% CI 4.33–5.19) days. Subperiod estimates varied temporally by nonpharmaceutical intervention type and fluctuating incidence.     

A Novel Collaborative Care Program to Augment Nursing Home Care During and After the COVID-19 Pandemic

The 2019 novel coronavirus (COVID-19) pandemic created an immediate need to enhance current efforts to reduce transfers of nursing home (NH) residents to acute care. Long-Term Care Plus (LTC+), a collaborative care program developed and implemented during the COVID-19 pandemic, aimed to enhance care in the NH setting while also decreasing unnecessary acute care transfers. Using a hub-and-spoke model, LTC+ was implemented in 6 hospitals serving as central hubs to 54 geographically associated NHs with 9574 beds in Toronto, Canada. LTC+ provided NHs with the following: (1) virtual general internal medicine (GIM) consultations; (2) nursing navigator support; (3) rapid access to laboratory and diagnostic imaging services; and (4) educational resources. From April 2020 to June 2021, LTC+ provided 381 GIM consultations that addressed abnormal bloodwork (15%), cardiac problems (13%), and unexplained fever (11%) as the most common reasons for consultation. Sixty-five nurse navigator calls addressed requests for non-GIM specialist consultations (34%), wound care assessments (14%), and system navigation (12%). One hundred seventy-seven (46%, 95% CI 41%-52%) consults addressed care concerns sufficiently to avoid the need for acute care transfer. All 36 primary care physicians who consulted the LTC+ program reported strong satisfaction with the advice provided. Early results demonstrate the feasibility and acceptability of an integrated care model that enhances care delivery for NH residents where they reside and has the potential to positively impact the long-term care sector by ensuring equitable and timely access to care for people living in NHs. It represents an important step toward health system integration that values the expertise within the long-term care sector.     

幼兔近视模型及大光明护眼液的疗效

目的 :探讨学生近视眼的发病机制和有效治疗药物。方法 :选用 2 0只新西兰纯种幼兔建立近视模型 ,然后分别采用2种药物和生理盐水治疗。结果 :大光明护眼液治疗组的平均屈光度 (D)值为 (+ 2 5 0± 0 6 8)、平均裸眼觅食距离 (cm)值为(2 80 0 0± 2 7 30 )、平均体重 (g)增长值为 (72 6 0 0± 31 30 ) ;而珍视明滴眼液治疗组和生理盐水治疗组近视屈光度 (D)值分别为(+ 1 6 6± 0 2 9)和 (+ 0 85± 0 42 ) ,平均裸眼觅食距离 (cm)分别为 (2 5 6 0 0± 5 4 48)和 (196 0 0± 76 48) ,平均体重 (g)增长分别为 (6 2 2 0 0± 31 94)和 (5 6 0 0 0± 6 2 85 )。结论 :(1)长期限制视距、微弱光线照射和经常习惯性近距离视物是造成近视眼的直接因素 ;(2 )采用大光明护眼液治疗近视眼的疗效明显 ,优于珍视明滴眼液和生理盐水治疗组 (P <0 0 1)。