White matter integrity after cannabidiol administration for treatment resistant epilepsy.

OBJECTIVE: The effects of individual cannabinoids on white matter integrity are unclear. Human studies have shown white matter maturation alterations in regular recreational cannabis users with the magnitude of these effects dependent on the age of exposure. However, studies have yet to determine which phytocannabinoids are most responsible for these changes. In the current study, we analyzed the effects of pharmaceutical grade cannabidiol oral solution (CBD; Epidiolex® in the U.S.; Epidyolex® in the EU; 100 mg/mL oral solution) on white matter integrity using diffusion MRI in patients with treatment resistant epilepsy (TRE). METHODS: 15 patients with TRE underwent 3 T diffusion MRI prior to receiving CBD and then again approximately 12 weeks later while on a stable dose of CBD for at least two weeks. DTI analyzes were conducted using DSI Studio and tract-based spatial statistics (TBSS). RESULTS: DTI analysis using DSI Studio showed significant increases in fractional anisotropy (FA) in the right medial lemniscus (p = 0.03), right superior cerebellar peduncle (p = 0.03) and the pontine crossing tract (p = 0.04); decreased mean diffusivity (MD) in the left uncinate fasciculus (p = 0.02) and the middle cerebellar peduncle (p = 0.04); decreased axial diffusivity (AD) in the left superior cerebellar peduncle (p = 0.05), right anterior limb of the internal capsule (p = 0.03), and right posterior limb of the internal capsule (p = 0.02); and decreased radial diffusivity (RD) in the middle cerebellar peduncle (p = 0.03) and left uncinate fasiculus (p = 0.01). The follow-up ANCOVA also yielded significant results when controlling for covariates of CBD dosage, age, sex, change in seizure frequency, and scanner type: FA increased in the pontine crossing tract (p = 0.03); RD decreased in the middle cerebellar peduncle (p = 0.04) and left uncinate fasciculus (p = 0.04). Subsequent TBSS analysis controlling for the same variables yielded no significant white matter differences between groups. CONCLUSION: These findings indicate relatively minor short-term effects of highly-purified plant-derived CBD on white matter structural integrity in patients with TRE.

Sex-related Differences in Stress Reactivity and Cingulum White Matter.

The prefrontal cortex and limbic system are important components of the neural circuit that underlies stress and anxiety. These brain regions are connected by white matter tracts that support neural communication including the cingulum, uncinate fasciculus, and the fornix/stria-terminalis. Determining the relationship between stress reactivity and these white matter tracts may provide new insight into factors that underlie stress susceptibility and resilience. Therefore, the present study investigated sex differences in the relationship between stress reactivity and generalized fractional anisotropy (GFA) of the white matter tracts that link the prefrontal cortex and limbic system. Diffusion weighted images were collected and deterministic tractography was completed in 104 young adults (55 men, 49 women; mean age = 18.87 SEM = 0.08). Participants also completed self-report questionnaires (e.g., Trait Anxiety) and donated saliva (later assayed for cortisol) before, during, and after the Trier Social Stress Test. Results revealed that stress reactivity (area under the curve increase in cortisol) and GFA of the cingulum bundle varied by sex. Specifically, men demonstrated greater cortisol reactivity and greater GFA within the cingulum than women. Further, an interaction between sex, stress reactivity, and cingulum GFA was observed in which men demonstrated a positive relationship while women demonstrated a negative relationship between GFA and cortisol reactivity. Finally, trait anxiety was positively associated with the GFA of the fornix/stria terminalis - the white matter pathways that connect the hippocampus/amygdala to the hypothalamus. These findings advance our understanding of factors that underlie individual differences in stress reactivity.

Regional variation in the mechanical properties of cortical bone from the porcine femur.

Despite the widespread use of porcine bone as a substitute for human bone in the development of surgical technique and the use of fixation devices, relatively few studies have reported on the mechanical behaviour of porcine long bones. Regional variation in the mechanical properties of cortical bone from porcine femora was investigated using three-point bending and cutting tests. Results were related to measurements of bone architecture and composition and Rutherford backscattering spectrometry (RBS) was used to calculate the calcium to phosphorus ratio. There was significant, but limited, regional variation in the strength of the femur with bone from the distal, posterior quadrant (241.4 ± 10.43 MPa) being significantly stronger than that of the lateral quadrant (162.3 ± 17.96 MPa). Cortical bone was also anisotropic; samples cut transverse to the bone's axis were around six times tougher than those cut parallel to the axis (p<0.05). This corresponded with a significant negative correlation between the Young's modulus and toughness when cut along the longitudinal axis. RBS analysis of cortical bone samples gave a Ca:P ratio of 1.37 ± 0.035, somewhat lower than that reported for cortical bone of adult human femora. These results indicate that the mechanical properties of cortical bone show significant, but limited, variation around the porcine femur and that this should be taken into consideration when sampling and choosing an appropriate animal model for orthopaedic biomechanics research.

Proof of concept percutaneous treatment system to enable fast and finely controlled ablation of biological tissue.

A prototype system has been developed for producing controllable ablation of spherical lesions with a diameter of up to 2 cm. The system is based on a solid-state energy source operating in the super high frequency (SHF is defined as being a frequency of between 3 and 30 GHz) region of the electromagnetic spectrum. Results obtained from preliminary tissue testing, performed on morbid tissue samples prepared in a laboratory environment, show repeatability in terms of shape and size of ablation, and demonstrate the ability to produce controlled ablation in morbid liver and kidney models.

Executive functioning in children with heavy prenatal alcohol exposure.

BACKGROUND: Children with heavy prenatal alcohol exposure have well documented deficits in overall cognitive ability. Recently, attention has turned to the executive function (EF) domain in this population. Until recently, comprehensive measures of EF have not been available within one test battery. This study used a battery of tests to assess four domains of EF in alcohol-exposed children. METHODS: The Delis-Kaplan Executive Function Scale was used to evaluate EF in 18 children with heavy prenatal alcohol exposure, with and without a diagnosis of fetal alcohol syndrome (FAS), and 10 nonexposed controls. Children ranged in age from 8 to 15 years. Measures from four domains of executive functioning were analyzed: planning ability, cognitive flexibility, selective inhibition, and concept formation and reasoning. Tasks consisted of primary EF measures as well as measures of secondary component skills. RESULTS: Alcohol-exposed children were deficient on EF measures compared with nonexposed controls. Furthermore, in most cases, children with and without the FAS diagnosis did not differ from one another. These deficits were not entirely explainable by concomitant deficits on component skills. Specific impairments were identified within the domains of planning and response inhibition, with additional deficits in abstract thinking and flexibility. CONCLUSIONS: Deficits in executive functioning were observed in alcohol-exposed children with or without the diagnosis of FAS and in the absence of mental retardation. Performance on these EF tasks provides insight into the cognitive processes driving overall performance and has implications for adaptive and daily functions. These results are consistent with anecdotal and empirical reports of deficits in behavioral control and with neuroanatomical evidence of volumetric reductions in structures within the frontal-subcortical system in children with heavy prenatal alcohol exposure.

Rural health professionals' satisfaction with a rehabilitation mobile outreach program.

OBJECTIVE: To assess the extent to which rural physicians and allied health professionals are satisfied with consultation services provided by an interdisciplinary rehabilitation outreach team. DESIGN: Descriptive survey. SETTING: A rehabilitation outreach team that travels to 14 rural communities in eastern and northern Ontario, Canada. SUBJECTS: Thirty-six rural physicians (response rate, 53.7%) and 62 allied health professionals (response rate, 92.5%) involved in the care of patients referred to the program. MAIN OUTCOME MEASURE: Consumer satisfaction questionnaire. RESULTS: Most respondents (94.7%) indicated that they were satisfied with the interdisciplinary consultation, with comparable rates of satisfaction reported by physicians and allied health professionals. The highest satisfaction ratings were given to items addressing the clarity of recommendations provided by team members and the quality of the team's interaction with patients. The lowest ratings were associated with the waiting time between visits. Of all the individual disciplines on the team, physiatry was rated as most important for rural consultations. However, in open-ended comments, respondents indicated that the interdisciplinary aspect of the service was its most valued characteristic, whereas infrequent visits were the greatest drawback. CONCLUSION: The interdisciplinary outreach approach to rehabilitation consultation receives high satisfaction ratings from rural health professionals who refer patients to the outreach team, which supports this model as a way to enhance rehabilitation services in rural communities.

Normative data for 4-year-old children on the California Verbal Learning Test-Children's Version.

This study presents normative data for 4-year-old children on the California Verbal Learning Test-Children's Version (CVLT-C), a measure of verbal learning and memory. Norms are currently available for children 5 years and older; however, normative data are unavailable for this younger population. Forty males and 40 females comprise this normative sample of 4-year-old children. The mean number of words recalled increased from the first to the fifth learning trial, and a consistent level of recall was maintained across delay recall trials. Extra-list intrusion responses were common and these responses were more frequent than correct responses on cued but not free recall conditions. Finally, yes/no recognition testing resulted in the greatest mean number of words remembered compared to the other trials. Overall, the pattern of performance across the learning and memory variables in this younger population was similar to that of older children, but at a lower level. These data suggest that 4-year-old children are able to perform this task, making possible the use of the CVLT-C in normal and clinical populations in this age group.

Hemodynamic effects of high-frequency oscillatory ventilation in children.

The purpose of this study was to evaluate the acute hemodynamic effects of transitioning a patient from conventional mechanical ventilation (CMV) to high-frequency oscillatory ventilation (HFOV). Our hypothesis was that hemodynamic status would not be adversely affected by such a change. Ten pediatric patients with acute hypoxemic respiratory failure and a thermodilution pulmonary arterial catheter in place were prospectively evaluated on the transition from CMV to HFOV. Hemodynamic and respiratory data were obtained before and within 1 hour of transition to HFOV with a "high-volume" ventilation strategy. On CMV, the mean oxygenation index of the patients was 18+/-4. Despite increases in mean airway pressure and decreases in mean arterial pressure and systemic vascular resistance on HFOV, there was no change in pulmonary circulation variables, cardiac index, or oxygen delivery. We concluded that in pediatric patients with acute respiratory failure and unstable cardiovascular status, the transition from CMV to HFOV was not accompanied by a decrease in cardiac function or oxygen delivery.

Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial.

PURPOSE: To study the efficacy and safety of various dosages of metformin as compared with placebo in patients with type II diabetes mellitus. PATIENTS AND METHODS: A 14-week, multicenter, double-blind, dose-response study was conducted. After a 3-week, single-blind, placebo-controlled washout, 451 patients with fasting plasma glucose levels of at least 180 mg/dL were randomized to receive an 11-week course of placebo or metformin given at 500, 1000, 1500, 2000, or 2500 mg daily. RESULTS: Metformin improved glucose variables as compared with placebo. The adjusted mean changes in fasting plasma glucose from baseline associated with each metformin group at week 7, 11, or at endpoint exceeded those associated with placebo by 19 to 84 mg/dL at dosages of 500 to 2000 mg daily, respectively. The corresponding between-group differences in glycated hemoglobin (HbA1c) ranged from 0.6% to 2.0% at dosages of 500 to 2000 mg daily, respectively. All between-group differences were significant (P < 0.05) for both fasting plasma glucose and HbA1c at week 7, week 11, and endpoint, except for the difference between placebo and metformin 500 mg in fasting plasma glucose at endpoint (P = 0.054). Treatment-related adverse events occurred in 15% of patients in the placebo group and in 28% in the metformin group (P = 0.02); these were primarily manifested as digestive disturbances, such as diarrhea. CONCLUSIONS: Metformin lowered fasting plasma glucose and HbA1c generally in a dose-related manner. Benefits were observed with as little as 500 mg of metformin; maximal benefits were observed at the upper limits of the recommended daily dosage. All dosages were well tolerated. Metformin appears to be a useful therapeutic option for physicians who wish to titrate drug therapy to achieve target glucose concentrations.

Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus.

This study was conducted to assess the effect of noninsulin-dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metformin and to investigate whether or not metformin exhibits dose-dependent pharmacokinetics. The pharmacodynamic effects (on plasma glucose and insulin) of metformin in patients with NIDDM and in healthy subjects also were assessed. Nine patients with NIDDM and 9 healthy subjects received 4 single-blind single-dose treatments of metformin HCL (850 mg, 1,700 mg, 2,550 mg, and placebo) and a multiple-dose treatment of 850 mg metformin HCL (3 times daily for 19 doses). After each single-dose treatment and the final dose of the multiple-dose phase, multiple plasma and urine samples were collected for 48 hours and assayed for metformin levels. Plasma samples were also assayed for glucose and insulin levels. There were no significant differences in metformin kinetics in patients with NIDDM compared with healthy subjects, in men compared with women, or during multiple-dose treatment versus single-dose treatment. Plasma concentrations of metformin increase less than proportionally to dose, most likely due to a decrease in percent absorbed. In patients with NIDDM, single doses of 1,700-mg or higher of metformin significantly decrease postprandial, but not preprandial, glucose concentrations and do not influence insulin concentrations. With multiple doses, both preprandial and postprandial glucose concentrations and preprandial insulin concentrations were significantly lower than with placebo. The effect of metformin on glucose level is correlated with the average fasting plasma glucose level without drug. In healthy subjects, single and multiple doses of metformin showed no effect on plasma glucose, but significantly attenuated the rise in immediate postprandial insulin levels.

Food intake and dosage level, but not tablet vs solution dosage form, affect the absorption of metformin HCl in man.

The pharmacokinetics of four single-dose treatments of the metformin administered orally (as the HCl salt) were compared in 24 healthy subjects: 500 mg and 850 mg tablets and 850 mg solution fasting and 850 mg tablet with food. Solution and tablet formulations are bioequivalent. Bioavailability of a 500 mg tablet is 14% greater than that of an 850 mg tablet. Compared with the fasting state, bioavailability is 24% lower, and the peak concentration delayed about 37 min when an 850 mg tablet is administered with food.

Kidney function and age are both predictors of pharmacokinetics of metformin.

The effects of renal impairment and age on the pharmacokinetics of metformin were evaluated. The subjects, including 6 young, 12 elderly, and 3 middle-age healthy adults and 15 adults with various degrees of chronic renal impairment (CRI) each were given a single, 850-mg metformin HCl tablet. Multiple whole blood, plasma, and urine samples were collected and analyzed for metformin levels using a high-performance liquid chromatography (HPLC) method. In healthy elderly individuals, the plasma and whole blood clearance/absolute bioavailability values [CL/F and (CL/F)b], and corresponding renal clearance values (CLR and CLR,b) of metformin were 35-40% lower than the respective values in healthy young individuals. These two groups did not differ significantly with respect to volume of distribution (Vd), time to peak concentration (tmax), and parameters related to metformin's appearance in the urine. In the moderate and severe CRI groups, all clearance values were 74-78% lower than in the healthy young/middle-age group, and all other evaluable pharmacokinetic parameters (with the exception of tmax) differed significantly in this group. In the mild CRI group, clearance values of metformin, which were 23-33% lower than in the young/middle-age group, were the only parameters that differed significantly. Based on a regression analysis of the combined data, both creatinine clearance (CL*cr; corrected for body surface area) and age are predictors of metformin clearance, with the following model best fitting the data: CL/F [or (CL/F)b, CLR, CLR,b] = alpha + beta.CL*cr + gamma.CL*cr.age. Metformin should not be used in patients with moderate and severe CRI, or in patients with mild, but not absolutely stable, renal impairment. The initial and maximum doses in elderly patients and patients with stable mild CRI should be lowered to approximately one third that given to the general (i.e., patients without non-insulin-dependent diabetes) population.

Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group.

BACKGROUND: Sulfonylurea drugs have been the only oral therapy available for patients with non-insulin-dependent diabetes mellitus (NIDDM) in the United States. Recently, however, metformin has been approved for the treatment of NIDDM. METHODS: We performed two large, randomized, parallel-group, double-blind, controlled studies in which metformin or another treatment was given for 29 weeks to moderately obese patients with NIDDM whose diabetes was inadequately controlled by diet (protocol 1: metformin vs. placebo; 289 patients), or diet plus glyburide (protocol 2: metformin and glyburide vs. metformin vs. glyburide; 632 patients). To determine efficacy we measured plasma glucose (while the patients were fasting and after the oral administration of glucose), lactate, lipids, insulin, and glycosylated hemoglobin before, during, and at the end of the study. RESULTS: In protocol 1, at the end of the study the 143 patients in the metformin group, as compared with the 146 patients in the placebo group, had lower mean (+/- SE) fasting plasma glucose concentrations (189 +/- 5 vs. 244 +/- 6 mg per deciliter [10.6 +/- 0.3 vs. 13.7 +/- 0.3 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.6 +/- 0.2 percent, P < 0.001). In protocol 2, the 213 patients given metformin and glyburide, as compared with the 210 patients treated with glyburide alone, had lower mean fasting plasma glucose concentrations (187 +/- 4 vs. 261 +/- 4 mg per deciliter [10.5 +/- 0.2 vs. 14.6 +/- 0.2 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.7 +/- 0.1 percent, P < 0.001). The effect of metformin alone was similar to that of glyburide alone. Eighteen percent of the patients given metformin and glyburide had symptoms compatible with hypoglycemia, as compared with 3 percent in the glyburide group and 2 percent in the metformin group. In both protocols the patients given metformin had statistically significant decreases in plasma total and low-density lipoprotein cholesterol and triglyceride concentrations, whereas the values in the respective control groups did not change. There were no significant changes in fasting plasma lactate concentrations in any of the groups. CONCLUSIONS: Metformin monotherapy and combination therapy with metformin and sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled with diet or sulfonylurea therapy alone.

Retinal abnormalities associated with anemia.

The incidence of clinically apparent retinal changes in 35 anemic patients and 35 age- and sex-matched control subjects was studied. Retinal photographs of all subjects were obtained. From these, all vascular and extravascular retinal lesions were noted. No retinal abnormalities were observed in the control subjects. Seven (20%) of the anemic patients exhibited extravascular lesions. There was no relationship detected between the occurrence of these changes and the severity or the cause of the anemia. Employing the assumption that true venous length for a given net distance traveled correlates with the degree of venous tortuosity, venous length over a standard radial distance from the optic disc was assessed with a curvometer. A significant negative correlation was determined between venous length and the level of hematocrit, thereby implying that retinal venous tortuosity is directly related to severity of anemia.

Azathioprine-induced pancytopenia. Occurrence in two patients with connective-tissue diseases.

Two patients became severely pancytopenic while receiving azathioprine in low dosages for treatment of connective-tissue diseases. While mild hematologic complications are common with this drug, we believe that the degree of bone marrow suppression exhibited in these two patients is unusual, especially at the dosages (0.75 and 1.25 mg/kg/day) of azathioprine being used.

Studies in B12-deficient monkeys with combined system disease. I. B12-deficient patterns in bone marrow deoxyuridine suppression tests without morphologic or functional abnormalities.

A colony of rhesus monkeys made vitamin B12 deficient through dietary deprivation has been maintained since 1970. Deficient animals regularly develop neurologic lesions histologically, ultrastructurally, and topographically indistinguishable from those of human subacute combined degeneration but have failed to develop overt hematologic changes. No megaloblastic alterations, other evidence of impaired blood cell production, or subtle differences in mean red cell size are found. dU suppression tests on bone marrow were performed to determine whether functional B12 deficiency existed. All B12-deficient monkeys had markedly abnormal dU suppression test results after more than 10 months of B12 depviation, corrected by addition of B12 in vitro, whereas controls remained normal. Reasons for these disparate findings are considered, including species differences in metabolism of cobalamin analogues, cobalamin, and transcobalamins; the sensitivity of the dU test; the fact that ability to utilize preformed nucleotides may be greater in monkeys than in humans.

Optical interference method for the approximate determination of refractive index and thickness of a transparent layer.

Optical interference fringe measurements of the thickness of transparent layers can be rapid, accurate, and nondestructive. If the refractive index n of the layer being measured is known, it may be combined directly with interference fringe information to yield the layer thickness t. If, however, n is unknown, the measurement procedure necessarily becomes more complicated. In this paper, a new and simpler optical interference method is presented for the approximate determination of both n and t of a transparent layer on a transparent substrate. The required experimental information is obtained from a single spectrophotometric recording of either the reflectance or transmittance of the layer and its substrate. The theory of the method is presented, and an application of the method to measurements of layers of SIPOS (Semi-Insulating POlycrystalline Silicon) is described. The method requires that the layer being measured must be uniformly deposited on a flat substrate, and it must neither absorb nor scatter the light passing through it. The major approximation inherent in the method is that both the layer and the substrate are assumed to be nondispersive over the wavelength region of interest.