Demonstration of synergistic effects of hyperthermia and photodynamic therapy using the chick chorioallantoic membrane model.

The chick chorioallantoic membrane (CAM) model was used to study vascular effects of photodynamic therapy (PDT) and hyperthermia (HPT) and the synergism of these modalities. The CAM is a convenient medium for monitoring the modifications of the vasculature. It is possible to view the CAM and to examine structural changes of individual blood vessels in real time. Moreover, the CAM is a closed system which lends itself to mathematical modeling of the temporal and spatial temperature profile and in which HPT can be performed quantitatively and to a selected depth, using different lasers. A porphyrin-type photosensitizer solution was applied to areas of the CAM, defined by teflon O-rings placed on the surface. Uptake dynamics of the sensitizer into the CAM was determined by analyzing its fluorescence in vivo. The CAM area was irradiated with a dual-wavelength laser system composed of a dye laser at 644 nm (to induce PDT) and a CO2 laser at 10.6 microns (to bring about HPT). Damage to the CAM vasculature, due to combined PDT+HPT, was compared to the outcome of the separate modalities, and a synergistic effect of about 40% was observed.     

N-substituted pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides. A new class of diuretics.

The synthesis and evaluation of a new class of diuretic agents derived from the pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide ring system are described. Preliminary structure-activity relationships indicate that the nature and location of the substituents at different positions of the heterocycle are crucial for activity. Thus, a novel synthetic methodology has been developed to selectively introduce the desired substituents at different positions. From the study of the pharmacological properties (dose-response curves, duration of action, and acute toxicity) of the most active compounds, 4-amino-1,7-diethyl-6-methylpyrazino[2,3-c][1,2,6]thiadiazine++ + 2,2-dioxide (9) was selected for further investigation. Compound 9 (C10H15N5O2S) crystallizes in space group P21/a with unit cell dimensions a = 16.482 (1), b = 9.3484 (3), c = 8.333 (3) A, beta = 103.003 (3) degrees, Z = 4.     

Efficacy evaluation of gadoteridol for MR angiography of intracranial vascular lesions

A phase III multicenter study was conducted in 89 patients with known intracranial vascular lesions to evaluate an extracellular gadolinium contrast agent, gadoteridol, for intracranial magnetic resonance (MR) angiography. The pre- and postcontrast MR angiograms of 82 patients were evaluated by the unblinded investigators and by two blinded readers (A and B) for visualization of lesions; arterial and venous anatomy; extent, size, and number of lesions; and disease classification. The unblinded readers indicated that lesions were visualized better on postcontrast images in the following categories: venous anatomy, 87 (81%) of 107 lesions; arterial anatomy, 43 lesions (40%); and extent or size of lesions, 38 lesions (36%). In 29 (35%) of 82 patients, the unblinded readers determined that enhanced MR angiography provided more diagnostic information than unenhanced MR angiography. The blinded readers determined that enhanced MR angiography provided more information for visualization of vascular anatomy in more than 60% of cases. The additional information provided with gadoteridol would have changed the diagnosis in nine (8%) of 107 lesions seen by the unblinded readers, 11 (12%) of 90 lesions seen by reader A, and three (3%) of 93 lesions seen by reader B. The results confirm that the use of gadoteridol improves the visualization of intracranial vascular lesions with MR angiography. The authors conclude that development of new postprocessing algorithms will improve the utility of contrast-enhanced MR angiography.     

Urodynamic assessment and lateral urethrocystography. A comparison of two diagnostic procedures for female urinary incontinence

We compared urodynamic findings and results of lateral urethrocystography in 84 case. The aim of the study was to establish a possible correlation between anatomic findings and functional results. Clinically, a significantly greater increase in the normal axis of urethral inclination was noted in patients with a urodynamic diagnosis of stress incontinence than in patients with urge incontinence or for normal urodynamic findings. Lateral urethrocystography vis-à-vis urodynamic assessment proved to be a method having high sensitivity (91%) but low specificity. These two methods supply different but complementary data. Together with the patients' medical history, the assessment of their complaints, clinical vaginal examination, and clinical stress test, they offer valuable information for an efficient therapeutic concept.     

Computed tomography in gunshot wounds to the neck: Can we predict vascular injury?

The purpose of this study was to evaluate the ability of helical computed tomography (CT) to detect arterial injuries in gunshot wounds to the neck. In a blinded retrospective review, 54 helical CT scans of the cervical spine were evaluated for bullet/bone fragments, subcutaneous air, bullet path, hematoma, spine fractures, and pharyngoesophageal compromise. The distance of fragments to a major vessel was calculated. CT findings that correlated significantly with major arterial injury included the presence of fragments (bullet/bone) close to a major vessel (2.5 mm) and spine fractures. Visualizing fragments <5 mm from a vessel or a transcervical bullet trajectory predicted 12 of 13 major arterial injuries. We conclude that CT clearly depicts anatomic damage. Specific findings, such as the location of fragments and bullet trajectory adjacent to a vessel and spine fractures, indicate a higher probability of vascular damage, thus directing more definitive evaluation.     

New insights on P2X purinoceptors

Significant advances in understanding of P_2X purinoceptor pharmacology have been made in the last few years. The limitations of nucleotide agonists as drug tools have now been amply demonstrated. Fortunately, inhibitors of the degrading ecto-ATPase enzymes are becoming available and it has become apparent that the complete removal of all divalent cations can be used experimentally in some systems to prevent nucleotide breakdown. Despite these issues, convincing evidence for P_2X receptor heterogeneity, from data with agonists, has recently been reported.A number of new antagonists at P_2X purinoceptors have also recently been described which to some degree appear to be more specific and useful than earlier antagonists like suramin. It is now apparent that suramin is a poor antagonist of ATP in many tissues because it potently inhibits ATPase activity at similar concentrations to those at which it blocks the P_2X purinoceptor.Advances in the use of radiolabelled nucleotides as radioligands for binding studies has allowed the demonstration of P_2X purinoceptors in a variety of tissues throughout the body including the brain. These studies have also provided evidence for receptor heterogeneity. Excitingly, two P_2X purinoceptor genes have been cloned but operational studies suggest that more than two types exist. The cloning studies have also demonstrated a unique structure for the P_2X purinoceptor which differentiates it from all other ligand-gated ion channel receptors. Further studies on P_2X purinoceptor operation and structure are needed to help resolve controversies alluded to regarding the characterization and classification of nucleotide receptors. Hopefully such studies will also lead to a better understanding of the physiological and pathological importance of ATP and its activation of P_2X purinoceptors. This will require the identification of better drug tools, in particular antagonists which may also provide the basis for novel therapeutic agents.     

Role of Alcohol-induced Hypothermia in Mediating the Teratogenic Effects of Alcohol in C57BL/6 J Mice

The purpose of this study was to determine the role of alcohol-induced maternal hypothermia in the teratogenic actions of alcohol. C57BL/6J mice were administered an acute dose of alcohol (5.8 g/kg orally) or isocaloric sucrose on day 10 of gestation. One half of each group was placed for 6 hr in an incubator set at 32 degrees C and the other half was housed in the incubator at room temperature (22 degrees C). As expected, acute prenatal alcohol exposure at this time of gestation was associated with decreased birth weight and an increase in limb and kidney malformations. The significant alcohol x environmental temperature interaction on these dependent variables indicated that the teratogenic insult was not attenuated, but was in fact even greater for the 32 degrees C/alcohol group. An absence of a main effect of environmental temperature indicated that the 32 degrees C environment, per se, was not teratogenic. Thus, maternal hypothermia is probably not an etiological factor in animal models of fetal alcohol syndrome. Moreover, antagonism of alcohol-induced maternal hypothermia exacerbates the teratogenic actions of alcohol observed at room temperature.     

Recall of medication during pregnancy: Validity and accuracy of an adjusted questionnaire

Objective — To study the validity and accuracy of an adjusted questionnaire on medical drug use during pregnancy eight years after the pregnancy. Methods — The ability of a questionnaire on medication during pregnancy to detect actual use (= sensitivity) was tested against information collected 8 years previously (in 1983–1984) from 473 women with high-risk pregnancies who delivered at the University Hospital Nijmegen, the Netherlands. Results — For separate drug groups, the sensitivity varied between 5% and 91%. The timing of use was recalled moderately well. Although specific questions on drug groups did improve the sensitivity as compared to an earlier questionnaire, the improvement was not enough to make the questionnaire valid. High maternal education, low birth weight, low gestational age and a low 5-min Apgar score were related to better recall. The sensitivity of the questionnaire depended on the behavioural score of the child, implying recall bias. Conclusion — Questionnaire data on drug use during pregnancy obtained eight years after delivery are not a valid source of information.     

G2019S LRRK2 mutation in familial and sporadic Parkinson's disease in Russia.

Among mutations associated with autosomal dominant and sporadic Parkinson's disease (PD) the G2019S substitution in the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequently identified. To estimate its frequency in Russia, we analyzed 208 patients with PD from the Northwestern region of Russia. Of these, 51 patients were probands from families with PD compatible with autosomal dominant inheritance. The control group represented 161 subjects without neurological disorders settled in the same region. The frequency of the G2019S mutation was greater in familial PD (2 [3.9%] of 51) than in sporadic PD (1 [0.6%] of 157). In addition, this mutation was found in the proband's father, who also had PD, in 1 PD family, and in 1 carrier without signs of PD at age 40 in another PD family. All carriers were heterozygous for the G2019S mutation and reported the Ashkenazi Jewish origin. The mutation was not found in the control group.     

Bromide intoxication secondary to pyridostigmine bromide therapy

The diagnosis of bromide intoxication is often aided by the detection of a low or negative anion gap due to the laboratory detection of bromide as chloride. A 59-year-old woman with myasthenia gravis who received a large dose of pyridostigmine bromide developed postoperative psychosis and was diagnosed as having bromide intoxication. The diagnosis was suspected in the setting of a negative anion gap and only later confirmed by direct measurement of the serum bromide level. To our knowledge , this is the first reported case of bromide intoxication due to pyridostigmine bromide administration.