Three-month Studies Research Articles

RISK REDUCTION ASSESSMENT: EPIDEMIOLOGY AND NOVEL APPROACHES

Introduction. Today, there are new approaches to assessing the potential impact of alternative nicotine delivery systems, such as systemic toxicology and biomarker assessment. The modern development of science and technology, including laboratory research, allows for a detailed assessment of the biological effects of a substance or complex of substances on the human body as a whole.
 The aim of the study: to compare and assess based on literature data possibility to broaden the standard approach for risk reduction assessment for lifestyle (potentially correctable) risk factors, especially tobacco smoking (TS). While epidemiology remains a golden standard for risk reduction assessment, novel approaches are based on preventive or system toxicology analysis and biomarkers of harm evaluation, thus it is crucial to understand both benefits and limitations of novel and standard approaches to complete risk reduction assessment for potentially correctable risk factors.
 Materials and methods. The thematic scientific papers, published predominantly during the last decade, constituted the study material. The research methodology involved bibliosemantic method and structural and logical analysis.
 Results and discussion. Level of modern scientific development already can help us to assess the harm made by new/emerging products based on epidemiological, toxicological data and evaluation of biomarkers of potential harm for specific risk or disease. For TS biomarkers of harm are mostly well established and include 15 Harmful and Potentially Harmful Constituents (HPHCs) of tobacco smoke and their metabolites in the body. Reduction in Total-3-OH-B[a]P, S-PMA, COHb and other can show reduction in harm and risk caused by new/emerging product. So far most comprehensive analysis of reduction in HPHCs and biomarkers manifestation was concluded for tobacco heating system as TS alternative. Switching from cigarettes to THS for 5 days resulted in 56 % to 96 % reductions in 15 exposure biomarkers in the THS group compared to the TS group. These values approached the decrease in effect observed in the group of complete refusal of TS. Similar observations were made for the 90-day studies, where the reduction observed on day 5 was maintained until the end of the three-month studies and confirmed by other 3 clinical studies.
 Conclusions. In general, the results of the risk reduction assessment based on novel approaches
 confirms that THS is an acceptable alternative to cigarettes for adult smokers, and based on the positive biological effects, the transition to THS represents a lower risk for the smoker’s body with regard to the effects of HPHCs.

In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease

Direct targeting of alpha-synuclein (ASYN) has emerged as a disease-modifying strategy for Parkinson’s disease and other synucleinopathies which is being approached using both small molecule compounds and ASYN-targeted biologics. Minzasolmin (UCB0599) is an orally bioavailable and brain-penetrant small molecule ASYN misfolding inhibitor in clinical development as a disease-modifying therapeutic for Parkinson’s disease. Herein the results of preclinical evaluations of minzasolmin that formed the basis for subsequent clinical development are described. Pharmacokinetic evaluations of intraperitoneal 1 and 5 mg/kg minzasolmin in wildtype mice revealed parallel and dose-proportional exposures in brain and plasma. Three-month administration studies in the Line 61 transgenic mouse model of PD were conducted to measure ASYN pathology and other PD-relevant endpoints including markers of CNS inflammation, striatal DAT labeling and gait. Reductions in ASYN pathology were correlated with improved aspects of gait and balance, reductions in CNS inflammation marker abundance, and normalized striatal DAT levels. These findings provide support for human dose determinations and have informed the translational strategy for clinical trial design and biomarker selection for the ongoing clinical studies of minzasolmin in patients living with early-stage Parkinson’s disease (ClinicalTrials.gov ID: NCT04658186; EudraCT Number 2020–003265).

Mindfulness, Spirituality, and Quality of Life among Cancer Survivors Undergoing Chemotherapy: Three-Month Observa-Tional Studies in Indonesia

Mindfulness, Spirituality, and Quality of Life among Cancer Survivors Undergoing Chemotherapy: Three-Month Observa-Tional Studies in Indonesia

Theophylline-nicotinamide pharmaceutical co-crystals generated using hot melt extrusion technology: Impact of polymeric carriers on processability

The objective of the current study was to develop theophylline (TPH) nicotinamide (NAM) pharmaceutical co-crystals using the hot melt extrusion (HME) technology and evaluate the processability of the co-crystals using different polymeric carriers. A physical mixture of 1:1 M ratio of TPH and NAM was employed to prepare the co-crystals. Hydroxypropylmethylcellulose acetate succinate, polyethylene oxide, and Kollidon® VA-64 (5% w/w) were investigated as polymeric carriers for the HME process. Solid-state characterization using differential scanning calorimetry showed two endothermal peaks, one at 126.4 °C indicating eutectic formation and another at 174 °C indicating the melting point of the co-crystal for all formulations, except the Kollidon® VA-64 extrudates, which showed a single peak at 174 °C. Fourier-transform infrared spectroscopy and powder X-ray diffraction studies revealed the formation of co-crystals. The feasibility to formulate the extrudates into solid dosage forms was assessed by formulating a tablet blend. The three-month stability studies showed no degradation at the accelerated stability conditions of 40 (±2) ° C and 75 (±5) % RH. Finally, the results demonstrated that the presence of mixing zones in screw configuration and extrusion temperature are critical processing parameters that influence co-crystal formation.

A survey of Hip Society surgeons concerning the direct anterior approach total hip arthroplasty.

To establish whether there was a consensus among the members of the Hip Society (HS) on the role of direct anterior approach (DAA) contemporary primary total hip arthroplasty (THA). An online survey was sent to all 112 active and senior members of the HS, to which 71 members responded. The survey was constructed to determine whether they believed that evidence-based medicine proves, in modern clinical practice, that the DAA has significant benefits compared to risks when contrasted with other approaches. In addition, they were asked if they currently used the DAA. While only 16.9% (12/71) of respondents had been trained in a generic anterior approach during residency, 49.3% (35/71) had used the DAA in their clinical practice in the past or were using it at the present time. Unexpectedly, 42.9% (15/35) of respondents who had used the DAA in the past had abandoned it by the time of this survey. Only 22.5% (16/71) of all respondents believed that evidence-based medicine proves that the DAA has significant benefits compared to risks in contrast to other approaches. A comprehensive literature review found only three prospective randomized clinical trials (RCT) comparing the DAA with another approach with greater than one-year follow-up. Two showed minor benefits within the early postoperative period only, and one of those showed poorer mid-term results. Most of the published comparison studies with short follow-up show longer surgical times and greater blood loss for the DAA, and many three-month comparison studies show higher complication rates for the DAA using a proprietary traction table. The complications included problems with wound healing, lateral femoral cutaneous nerve injury, femoral component loosening, and femoral fractures. Because of the lack of evidence from RCTs showing superiority of the DAA over other approaches and reports of higher complications, the opinion of a large majority (77.5%; 55/71) of HS surgeons was that the DAA lacks sufficient evidence to warrant its use. Cite this article: Bone Joint J 2020;102-B(7 Supple B):57-61.

ОСОБЛИВОСТІ ВПРОВАДЖЕННЯ ЕЛЕКТРОННОГО ПОСІБНИКА З НАВЧАННЯ АНГЛІЙСЬКОЇ МОВИ У ДЕРЖАВНІЙ ПРИКОРДОННІЙ СЛУЖБІ УКРАЇНИ

У статті представлено аналіз результатів впровадження електронного посібника (ЕП) «Англійська мова для прикордонників» у навчальних закладах Державної прикордонної служби України (ДПСУ) та пунктах пропуску через державний кордон. В експерименті взяли участь 298 прикордонників, які навчались на тримісячних курсах інтенсивного вивчення англійської мови в Національній академії Державної прикордонної служби України імені Богдана Хмельницького, та 1158 осіб після завершення навчання на дистанційних курсах вивчення англійської мови в навчальних центрах ДПСУ. Анкетування проводилось за такими блоками: варіанти використання ЕП, вікові групи та статева приналежність, вихідний рівень іншомовної підготовки користувачів, загальні враження користувачів від роботи з ЕП, досвід використання, структура та користування ЕП, рівень удосконалення мовленнєвих навичок користувачів, ступінь насиченості розділів навчальним матеріалом, характеристика вправ ЕП. Аналіз анкет зворотного зв’язку та результатів опитування доводить, що реалізація ЕП в ДПСУ була успішною і відповідає особливим потребам прикордонників, що працюють у пунктах пропуску через державний кордон України, оскільки він був спеціально розроблений діючими представниками прикордонних відомств для подальшого використання прикордонниками. Оцінка результатів використання ЕП прикордонниками довела ефективність удосконалення іншомовної підготовки, необхідної для виконання прикордонниками повсякденних завдань, шляхом використання навчальних відео- й аудіоматеріалів, які відповідають справжнім ситуаціям на робочому місці представника прикордонного відомства. У результаті проведеного аналізу анкет було з’ясовано, що практична більшість респондентів (93%) погоджуються і усвідомлюють важливість вивчення англійської мови та вдосконалення іншомовних мовленнєвих навичок з метою спрощення виконання завдань у пунктах пропуску через державний кордон під час інтерв’ювання іноземців і участі в спільних міжнародних операціях. Водночас 7% користувачів частково або цілком не погоджуються з даним твердженням, що обумовлюється, насамперед, тим фактом, що ЕП виявився для них занадто складним через їх особистий низький рівень базової підготовки з англійської мови. Використання ЕП надало змогу прикордонникам легше і більш впевнено спілкуватися з пасажирами, що перетинають державний кордон, з’ясовувати обставини порушення законодавства й ефективно спілкуватись зі своїми колегами з інших європейських країн.

Inferior thalamic peduncle deep brain stimulation for treatment-refractory obsessive-compulsive disorder: A phase 1 pilot trial

BackgroundSeveral different surgical procedures targeting the limbic circuit have been utilized for severe, treatment resistant obsessive-compulsive disorder; however, there has only been limited exploration of the inferior thalamic peduncle (ITP). The aim of this study was to determine the safety and initial efficacy of ITP deep brain stimulation (DBS) in patients with severe obsessive-compulsive disorder. MethodsPatients with severe, treatment-refractory obsessive-compulsive disorder were enrolled into this open-label phase 1 DBS pilot study. Bilateral ITP DBS devices were implanted between November 2010 and December 2015. The primary outcome was safety. The initial efficacy was determined by Yale-Brown Obsessive-Compulsive scale (YBOCs) scores. Component Y-BOCs scores, Hamilton Depression Severity Scale, Quality of Life Assessment (SF-36), Oxford Happiness Questionnaire, Warwick-Edinburgh Mental Well-Being Scale, and Sheehan Disability Scale were also analyzed for a minimum of 2 years after surgery. Additionally, preoperative and three-month postoperative FDG-PET studies were performed on two patients. ResultsFive patients (2 males, 3 females; age range 25–48 years) received ITP DBS. All five patients were considered responders at one year (52% improvement in YBOCs scores compared to baseline (range 39–73%, p < 0.01) and last follow-up (54% improvement; range 38–85%; p < 0.01). At two years follow-up, there were three adverse events that occurred in two patients. One patient had his DBS system removed after one year due to the device becoming the object of his obsession. The other two adverse events were not related to the device. Post-operative FDG-PET imaging in two patients demonstrated decreased glucose uptake within the right caudate, right putamen, right supplementary motor area, and right cingulum and increased glucose uptake in bilateral motor areas, left temporal pole, and left orbitfrontal cortex. ConclusionsITP DBS has a favorable safety profile and is potentially an efficacious treatment for severe obsessive-compulsive disorder. Larger clinical trials are necessary to determine efficacy.

Oil-Infused Superhydrophobic Silicone Material for Low Ice Adhesion with Long-Term Infusion Stability.

A new approach for anti-icing materials was created to combat the effects of ice accretion and adhesion. The concept combines the strengths of individual characteristics for low ice adhesion based on elasticity, superhydrophobicity, and slippery liquid infused porous surfaces (SLIPS) for an optimal combination of high water repellency and ice-phobicity. This was achieved by replicating microtextures from a laser-irradiated aluminum substrate to an oil-infused polydimethylsiloxane (PDMS) elastomer, the result of which is a flexible, superhydrophobic, and lubricated material. This design provides multiple strategies of icing protection through high water repellency to retard ice accretion and with elasticity and oil infusion for low ice adhesion in a single material. Studies showed that an infusion of silicone oils with viscosity at 100 cSt and below 8 wt % in PDMS solution is sufficient to reduce the ice shear strength to an average of 38 kPa while maintaining contact angles and roll-off angles of above 150° and below 10°, respectively. This ice-adhesion value is a ∼95% reduction from a bare aluminum surface and ∼30% reduction from a microtextured, superhydrophobic PDMS material without oil infusion. In addition, three-month aging studies showed that the wetting and ice-adhesion performance of this material did not significantly degrade.

Pyrogallol-associated dermal toxicity and carcinogenicity in F344/N rats and B6C3F1/N mice

Pyrogallol (CAS No. 87-66-1), a benzenetriol used historically as a hair dye and currently in a number of industrial applications, was nominated to the National Toxicology Program (NTP) for testing based on the lack of toxicity and carcinogenicity data. Three-month and two-year toxicity studies to determine the toxicity and carcinogenicity of pyrogallol when applied to naïve skin (i.e. dermal administration) were conducted in both sexes of F344/N rats and B6C3F1/N mice. In the three-month studies, adult rodents were administered pyrogallol in 95% ethanol five days per week for 3 months at doses of up to 150 mg/kg body weight (rats) or 600 mg/kg (mice). Based on the subchronic studies, the doses for the two-year studies in rats and mice were 5, 20 and 75 mg/kg of pyrogallol. All mice and most rats survived until the end of the three-month study and body weights were comparable to controls. During the two-year study, survival of dosed rats and male mice was comparable to controls; however survival of 75 mg/kg female mice significantly decreased compared to controls. The incidences of microscopic non-neoplastic lesions at the site of application were significantly higher in all dosed groups of rats and mice and in both the 3-months and two-year studies. In the two-year study, hyperplasia, hyperkeratosis and inflammation tended to be more severe in mice than in rats, and in the mice they tended to be more severe in females than in males. The incidence of squamous cell carcinoma at the site of application (SOA) in 75 mg/kg female mice and SOA squamous cell papillomas in 75 mg/kg male mice were greater than controls. Pyrogallol was carcinogenic in female mice and may have caused tumors in male mice.

A Comparison of the Speed, Success Rate, and Retention of Rescue Airway Devices Placed by First-responder Emergency Medical Technicians: A High-fidelity Human Patient Simulation Study

BackgroundCurrent airway management for most first-responder basic emergency medical technicians (EMT-Bs) does not include the use of blind-advanced-airway devices. ObjectiveTo compare the speed, success rates, and skill retention with which EMT-Bs providers can place three blind-advanced-airway devices. MethodsProspective study of 43 EMT-Bs trained in the use of the Esophageal-Tracheal-Combitube® (ETC), King LT® (KLT), and Laryngeal Mask Airway™ (LMA). The time it took each participant to place each device correctly and ventilate a human patient simulator was assessed. Primary outcome measures were the success rate of proper insertion for each device and time interval from initiation of mouth insertion to initiation of chest rise. To assess skill retention, at 3 months the providers were reassessed under exact conditions. ResultsAt Day 1, time required to place an ETC, LMA, and KLT were 32.7 ± 12.3, 19.2 ± 6.2, and 20.1 ± 6.6 s, respectively. Using paired t-tests, LMA and KLT were faster than ETC, p < 0.0001. At 3 months, pair-wise comparisons showed the ETC took longer to place than the KLT and LMA, p < 0.0001; and the LMA took longer to place than the KLT, p = 0.0034 (36.4 ± 13.1 ETC, 24.8 ± 12.4 LMA, 19.0 ± 6.9 KLT). There was no statistical difference of failures in placing any device. ConclusionsComparison of three rescue airway devices placed by EMT-Bs providers showed that it takes significantly longer to place an ETC compared to an LMA and KLT both on Day 1 and 3 months later. Three-month retention studies revealed that it took significantly longer to place an LMA compared to the KLT.

A cross-cultural study on meaning and the nature of children's experiences in Australian and French swimming clubs

This article reports on a study conducted in Australia and France that inquired into the meaning and the nature of children's experiences of being in swimming clubs with a focus on the positive aspects of membership that keep them in their clubs. Three-month long case studies were conducted in a club in Australia and in a club in France, employing Lave and Wenger's (1991) analytic concepts of communities of practice and situated learning. Conducting case studies within two different socio-cultural settings allowed for the identification of common themes that transcend very different institutional and cultural settings while highlighting contextual factors and the situated nature of learning.

Effects of the PPARα Agonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism.

Gemfibrozil is a widely prescribed hypolipidemic agent in humans and a peroxisome proliferator and liver carcinogen in rats. Three-month feed studies of gemfibrozil were conducted by the National Toxicology Program (NTP) in male Harlan Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters, primarily to examine mechanisms of hepatocarcinogenicity. There was morphologic evidence of peroxisome proliferation in rats and mice. Increased hepatocyte proliferation was observed in rats, primarily at the earliest time point. Increases in peroxisomal enzyme activities were greatest in rats, intermediate in mice, and least in hamsters. These studies demonstrate that rats are most responsive while hamsters are least responsive. These events are causally related to hepatotoxicity and hepatocarcinogenicity of gemfibrozil in rodents via peroxisome proliferator activated receptor-α (PPARα) activation; however, there is widespread evidence that activation of PPARα in humans results in expression of genes involved in lipid metabolism, but not in hepatocellular proliferation.

Evaluation of the chondroprotective effect of mutual prodrug of diacerein in monosodium iodoacetate-induced osteoarthritis in Wistar rats

We have reported synthesis and in vitro release studies of a gastro-sparing mutual prodrug of diacerein with the nutraceutical aminosugar; Dglucosamine as a promoiety. The results of preliminary pharmacological screening were promising which prompted us to evaluate its potential for long-term use in the safer management of osteoarthritis. This work reports the results of three-month extensive studies in monosodium iodoacetate- induced osteoarthritis in wistar rats. The prodrug significantly reduced knee diameter and serum alkaline phosphatase to the baseline levels on the 60th day of drug intervention maintaining both the effects even on the 90t h day of drug intervention. In contrast, diacerein displayed no effect on the knee diameter till the 90 th day of drug intervention while a decreasing effect on serum alkaline phosphatase levels was displayed on the 15th day of drug intervention but was not maintained till the end of the study. Pretreatment with diacerein for 90 days significantly decreased the mean serum glycosaminoglycan level to the baseline value to the extent of 84-92% while the prodrug's reducing effect was in the range of 74-94%. Histopathological findings of the cartilage were assessed by osteoarthritis grading score in which the prodrug displayed better chondroprotection than diacerein.

The Influence of Fluoride Ions upon Selected Enzymes of Protein Metabolism in Blood Plasma of Rabbits with Hypercholesterolemia

Three-month studies were performed on 18 adult rabbits of New Zealand breed divided into three groups, with six animals in each: a control group on standard diet, a cholesterol group receiving 500 mg of cholesterol/100 g of feed per rabbit per 24 h (CH group), and a cholesterol + fluorine group (CH + F group) receiving 500 mg of cholesterol/100 g of feed per rabbit per 24 h and 3 mg of F(-)/kg of body weight per 24 h. The conducted studies proved that cholesterol in the applied dosage (500 mg cholesterol per rabbit per 24 h) has an atherogenic action. Fluoride ions administered together with a 500-mg cholesterol atherogenic diet inhibit the atheromatosic changes in the aorta. The concentration of plasma cholesterol was elevated in both study groups when compared to the control group but decreased in the CH + F group when compare to the CH group. The influence of fluoride ions has been examined upon the activity of alanine aminotransferase, aspartate aminotransferase, and glutamate dehydrogenase (GLDH) in the plasma in the liver of rabbits in the course of experimental hypercholesterolemia. Increase in the activity of study enzymes has been observed in the blood plasma, which may be due to damage occurring to hepatocytes of the animals examined (a statistically significant increase in the activity of GLDH in the plasma). In the liver, the inhibition of activity for all examined enzymes has been observed in the group of rabbits with hypercholesterolemia, which testifies the disturbances in protein metabolism in examined animals. The addition of sodium fluoride to the diet rich in cholesterol results in "removing the block" on those activities, which increase. We suppose that the permeability of the hepatocyte membrane was elevated, so the activities of examined enzymes increased in the plasma ("escape" to plasma). On the one hand, fluoride ions result in probable lesion of hepatocytes membranes; on the other hand, they inhibit the atheromatosic changes in the aorta.

Comparison of Off-line and On-line Measurement of Partial Discharges for Hydrogenerator Stator Windings using Acoustic Emission Sensors

The establishment of Condition Based Maintenance for hydrogenerators is very important for monitoring the conditions of stator windings insulation. On-line partial discharge (PD) testing has been used to provide useful information for monitoring the integrity and diagnosing problems in hydrogenerator stator winding insulation. The on-line insulation diagnosis technology can assess thermal, electric, ambient, and mechanical stresses received by the hydrogenerator stator windings. We have already indicated in a previous study that on-line PD measurements using acoustic emission sensor (AE) techniques can be useful for assessing the conditions of stator winding insulation. In this paper, the relationship between AE signals and maximum discharge magnitude was investigated in a non-destructive test for hydrogenerators using off-line measurements. AE signals were investigated by the use of multiple AE sensors, which are produced from an internal discharge for two hydrogenerator stator windings in 11kV and 13.2kV classes, in addition to the load and temperature, and humidity measurements taken on-line in twenty-month and three-month long studies respectively.

Toxicology and carcinogenesis studies of microencapsulated trans-cinnamaldehyde in rats and mice

trans-Cinnamaldehyde is a widely used natural ingredient that is added to foods and cosmetics as a flavoring and fragrance agent. Male and female F344/N rats and B6C3F 1 mice were exposed to microencapsulated trans-cinnamaldehyde in the feed for three months or two years. All studies included untreated and vehicle control groups. In the three-month studies, rats and mice were given diets containing 4100, 8200, 16,500, or 33,000 ppm trans-cinnamaldehyde. In rats, feed consumption was reduced in all exposed groups. In mice, feed consumption was reduced in the highest dose groups. Body weights of all treated males were less than controls. Body weights were reduced in female rats exposed to 16,500 or 33,000 ppm and female mice exposed to 8200 ppm or greater. All rats survived to the end of the study but some male mice in the highest dose groups died due to inanition from unpalatability of the dosed feed. The incidence of squamous epithelial hyperplasia of the forestomach was significantly increased in rats exposed to 8200 ppm or greater and female mice exposed to 33,000 ppm. In mice, the incidence of olfactory epithelial degeneration of the nasal cavity was significantly increased in males and females exposed to 16,500 ppm and females exposed to 33,000 ppm. In the two-year studies, rats and mice were exposed to 1000, 2100, or 4100 ppm trans-cinnamaldehyde. Body weights were reduced in mice exposed to 2100 ppm and in rats and mice exposed to 4100 ppm. In rats, hippuric acid excretion was dose proportional indicating that absorption, metabolism, and excretion were not saturated. No neoplasms were attributed to trans-cinnamaldehyde in rats or mice. Squamous cell papillomas and carcinomas of the forestomach were observed in male and female mice but the incidences were within the NTP historical control range and were not considered to be related to trans-cinnamaldehyde exposure.

Late arterial responses (6 and 12 months) after (32)P beta-emitting stent placement: sustained intimal suppression with incomplete healing.

Three-month studies of stent-delivered brachytherapy in the rabbit model show reduced neointimal growth. However, intimal healing is delayed, raising the possibility that intimal inhibition is merely delayed rather than prevented. The purpose of this study was to explore the long-term histological changes after placement of beta-emitting radioactive stents in normal rabbit iliac arteries. Three-millimeter beta-emitting (32)P stents (6, 24, and 48 microCi) were placed in normal rabbit iliac arteries with nonradioactive stents as controls. Animals were euthanatized at 6 and 12 months, and histological assessment, morphometry, and analysis of endothelialization were performed. Morphometric measurements demonstrated a >50% reduction in intimal growth and percent lumen stenosis within 24- and 48-microCi stents versus control nonradioactive stents at both 6 and 12 months. However, the 24- and 48-microCi stents also showed delayed healing of the intimal surface, characterized by persistent fibrin thrombus with nonconfluent areas of matrix, incomplete endothelialization, and increased intimal cellular proliferation. Stent edge stenosis was present at 12 months in the 24- and 48-microCi stent groups, characterized by both intimal thickening and negative arterial remodeling. Inhibition of intimal growth is maintained 6 and 12 months after (32)P beta-emitting stent placement. However, delayed arterial healing, incomplete endothelialization, and edge effects are present.

Sociality in the gray mouse lemur (Microcebus murinus) in northwestern Madagascar.

The mating system and social organization of the gray mouse lemur (Microcebus murinus) was investigated in two three-month field studies (covering a period before, during, and after the first mating season) in Ampijoroa, northwestern Madagascar. The spatial and temporal distribution of the sexes within a population was studied using mark/recapture techniques and radiotelemetry to assess possible contest or scramble competition between the males. Sociality was inferred from the occurrence and probability of nocturnal social encounters, the temporal stability of daily sleeping groups, and nocturnal ranging patterns of co-sleepers. Males and females were evenly distributed in the study area within a network of highly overlapping home ranges. No indications were found for the spatial monopolization of the females by certain dominant males. Males and females had spatial access to several potential mates; the mating system is therefore characterized as a multi-male/multi-female system. Male home range sizes increased during the first mating season, which was interpreted as an indicator for scramble competition between the males. Competitive mate searching, sperm competition, and temporary mate guarding as well as female mate choice are suggested as the most probable reproductive strategies. Over the course of the study the animals lived continually within the study area, and most females formed stable individualized sleeping associations. Females that slept together shared a higher percentage of their home range than did females that slept at different sites. It is suggested that this network of social relationships should be described as a dispersed but individualized neighborhood.

Stereotactic radiosurgical pallidotomy and thalamotomy with the gamma knife: MR imaging findings with clinical correlation--preliminary experience.

To evaluate the temporal evolution and appearance of a radiosurgical lesion at magnetic resonance (MR) imaging and the clinical response in patients undergoing stereotactic radiosurgical pallidotomy or thalamotomy with the gamma knife. Seventeen patients with medically refractory movement disorders underwent stereotactic radiosurgical pallidotomy (n = 2) or thalamotomy (n = 15). A single dose of 120-140 Gy was administered to a target in the globus pallidus interna or ventralis intermedius thalamic nucleus. Postprocedure gadolinium-enhanced MR imaging and clinical assessment were performed at 1 month and 3 months. At 3 months, the radiosurgical lesion most commonly (n = 11) appeared as a ring-enhancing focus 5 mm or less in diameter surrounded by vasogenic edema that extended less than 7 mm in radius beyond the target. Five patients had ring-enhancing lesions 7 mm or more in diameter; four of these developed symptomatic perilesional edema at 3 (n = 2) or 8 (n = 2) months after the procedure. Onset of therapeutic effect began approximately 4 weeks after treatment. In the 15 patients with tremor, there was a mean decline of 2.1 on the Tremor Rating Scale. Findings in this pilot study suggest that radiosurgical thalamotomy is a promising treatment for medically refractory tremor. Three-month follow-up MR studies show a ring-enhancing lesion surrounded by a variable amount of vasogenic edema. Visualization of the radiosurgical lesion and the clinical response are delayed compared to that with radio-frequency procedures.

Reversible induction of mucous cell hyperplasia and parietal cell loss in rats dosed with DMP-777

Parietal cell loss and mucous cell hyperplasia are important histological components of a spectrum of gastric mucosal diseases including Menetrier's disease and fundic H. pylori gastritis. Recent investigations using transgenic mouse strains have highlighted the importance of intrinsic mucosal growth factors such as TGFct in the differentiation of specific cell lineages in the gastric mucosa. Unfortunately, experiments in transgenic mice have been hampered by the irreversibility of atrophic-gastritis phenotypes. In three-month toxicity studies in rats, oral dosing with DMP-777 (50-200 mg/kg/day), a neutrophil elastase inhibitor, resulted in an unexpected phenotype of gastric mucous cell hyperplasia and parietal cell loss associated with hypergastrinemia. Routine histological staining (diastase-resistant PAS) and immunocytochemistry for BrdU, H/K-ATPase, spasmolytic peptide, gastrin, somatostatin and chromogranin A were utilized to determine alterations in mucosal lineages. Rats did not demonstrate any significant inflammatory infiltrate. Fundic mucosa demonstrated a prominent hyperplasia of surface mucous cells, 4 to 8-fold increases in isthmus zone BrdU-labeling index and a profound decrease in the numbers of parietal ceils, chief cells, somatostatin ceils and ECL ceils after 9 days of dosing with 200 mg/kg/day. The numbers of mucous neck cells were unaffected by drug treatment. Hyperplasia of gastrin cells was seen in the gastric antrum, but there was no hyperplasia of antral mucous cells. These changes were completely reversible after a threemonth drug-free recovery period. To examine the marked hypergastrinemia observed in DMP 777-treated rats, the effects of the drug on acid secretion were studied in the rat pylorus-ligation model, where DMP-777 was shown to be a potent inhibitor of gastric acid secretion when dosed orally. Additional in vitro tests showed that DMP-777 did not block histamine (H2), acetylcholine (M3) or gastrin receptors (novel and CCK-B receptors). In isolated rabbit parietal cells, 3 pM DMP-777 completely inhibited basal, histaminestimulated and forskolin-stimulated aminopyrine accumulation (ECso---0.6 pM). While the drug had no direct effect on the activity of the H/K-ATPase, 1-3 laM DMP-777 could dissipate completely an established stimulated proton gradient in isolated tubulovesicles loaded with acridine orange. These latter results suggest that DMP-777 is a protonophore. Since other regions of the gastrointestinal mucosa are not affected by the drug, unexpected effects of DMP-777 on the gastric mucosa may be due to a specific interaction with parietal cell, perhaps involving a specific partitioning of the drug into the parietal cell secretory canalicolus. Short term DMP-777 dosing of rats provides the first readily reversible model of parietal cell loss and mucous cell hyperplasia. This work was funded by DuPont-Merck Pharmaceuticals.