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Gliomas harboring oncogenic ROS1 alterations are uncommon and primarily described in infants. Our goal was to characterize the clinicopathological features and molecular signatures of the full spectrum of ROS1 fusion-positive gliomas across all age groups. Through a retrospective multi-institutional collaboration, we report a collection of unpublished ROS1 fusion gliomas along with the characterization and meta-analysis of new and published cases. A cohort of 32 new and 58 published cases was divided into the following 3 age groups: 19 infants, 40 pediatric patients, and 31 adults with gliomas. Tumors in infants and adults showed uniformly high-grade morphology; however, tumors in pediatric patients exhibited diverse histologic features. The GOPC::ROS1 fusion was prevalent (61/79, 77%) across all age groups, and 10 other partner genes were identified. Adult tumors showed recurrent genomic alterations characteristic of IDH wild-type glioblastoma, including the +7/-10/CDKN2A deletion; amplification of CDK4, MDM2, and PDGFRA genes; and mutations involving TERTp, TP53, PIK3R1, PIK3CA, PTEN, and NF1 genes. Infant tumors showed few genomic alterations, whereas pediatric tumors showed moderate genomic complexity. The outcomes were significantly poorer in adult patients. Although not statistically significant, tumors in infant and pediatric patients with high-grade histology and in hemispheric locations appeared more aggressive than tumors with lower grade histology or those in nonhemispheric locations. In conclusion, this study is the largest to date to characterize the clinicopathological and molecular signatures of ROS1 fusion-positive gliomas from infant, pediatric, and adult patients. We conclude that ROS1 likely acts as a driver in infant and pediatric gliomas and as a driver or codriver in adult gliomas. Integrated comprehensive clinical testing might be helpful in identifying such patients for possible targeted therapy., (Copyright © 2023. Published by Elsevier Inc.)

The 2021 WHO Classification of Tumors of the Central Nervous System includes several tumor types and subtypes for which the diagnosis is at least partially reliant on utilization of whole genome methylation profiling. The current approach to array DNA methylation profiling utilizes a reference library of tumor DNA methylation data, and a machine learning-based tumor classifier. This approach was pioneered and popularized by the German Cancer Research Network (DKFZ) and University Hospital Heidelberg. This research group has kindly made their classifier for central nervous system tumors freely available as a research tool via a web-based portal. However, their classifier is not maintained in a clinical testing environment. Therefore, the Northwestern Medicine (NM) classifier was developed and validated. The NM classifier was validated using the same training and validation data sets as the DKFZ group. Using the DKFZ validation data set, the NM classifier's performance showed high concordance (92%) and comparable accuracy (specificity 94.0% versus 84.9% for DKFZ, sensitivity 88.6% versus 94.7% for DKFZ). Receiver-operator characteristic curves showed areas under the curve of 0.964 versus 0.966 for NM and DKFZ classifiers, respectively. In addition, in-house validation was performed and performance was compared using both classifiers. The NM classifier performed comparably well and is currently offered for clinical testing., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Rab GTPases are essentially molecular switches. They serve as master regulators in intracellular membrane trafficking from the formation and transport of vesicles at the originating organelle to its fusion to the membrane at the target organelle. Their functions are diversified and each has their specific subcellular location. Their expression may vary significantly in the same cell when the level of protein production is significantly different in different physiologic status. One of the best examples is the transition from fetal to mature status of cells. Expression and localization of Rab GTPases in mature and developing brains have not been well studied. Immunohistochemistry is an efficient way in the detection, semiquantitation, and localization of Rab GTPases in tissue sections. It is inexpensive and fast which allow efficient mass screening of many sections. In this chapter, we describe the immunohistochemical assay protocol for analyzing several Rab protein expressions of the Rab5 subfamily, including Rab5, Rab17, Rab22, and Rab31, in developmental (fetal) and mature human brains., (© 2021. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Metastases from primary breast cancer result in poor survival. βIII-tubulin (TUBB3) has been established as a therapeutic target for breast cancer metastases specifically to the brain. In this study, we conducted a systematic analysis to determine the regulation of TUBB3 expression in breast cancer metastases to the brain and strategically target these metastases using vinorelbine (VRB), a drug approved by the U.S. Food and Drug Administration (FDA). We found that human epidermal growth factor receptor 2 (HER2) signaling regulates TUBB3 expression in both trastuzumab-sensitive and trastuzumab-resistant neoplastic cells. We further discovered that bromodomain and extra-terminal domain (BET) inhibition increases TUBB3 expression, rendering neoplastic cells more susceptible to apoptosis by VRB. Orthotopic xenograft assays using two different breast cancer cell models revealed a reduction in tumor volume with BET inhibition and VRB treatment. In addition, in vivo studies using a model of multiple brain metastasis (BM) showed improved survival with the combination of radiation + BET inhibitor (iBET-762) + VRB (75% long-term survivors, P < 0.05). Using in silico analysis and BET inhibition, we found that the transcription factor myeloid zinc finger-1 (MZF-1) protein binds to the TUBB3 promoter. BET inhibition decreases MZF-1 expression and subsequently increases TUBB3 expression. Overexpression of MZF-1 decreases TUBB3 expression and reduces BM in vivo, whereas its knockdown increases TUBB3 expression in breast cancer cells. In summary, this study demonstrates a regulatory mechanism of TUBB3 and provides support for an application of BET inhibition to sensitize breast cancer metastases to VRB-mediated therapy., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The power and widespread use of next-generation sequencing (NGS) in surgical neuropathology has raised questions as to whether NGS might someday fully supplant histologic-based examination. We therefore sought to determine the feasibility of relying on NGS alone for diagnosing infiltrating gliomas. A total of 171 brain lesions in adults, all of which had been analyzed by GlioSeq NGS, comprised the study cohort. Each case was separately diagnosed by 6 reviewers, based solely on age, sex, tumor location, and NGS results. Results were compared with the final integrated diagnoses and scored on the following scale: 0 = either wrong tumor type or correct tumor type but off by 2+ grades; 1 = off by 1 grade; 2 = exactly correct. Histology alone was treated as a seventh reviewer. Overall reviewer accuracy ranged from 81.6% to 94.2%, while histology alone scored 87.1%. For glioblastomas, NGS was more accurate than histology alone (93.8%-97.9% vs 87.5%). The NGS accuracy for grade II and III astrocytoma and oligodendroglioma was only 54.3%-84.8% and 34.4%-87.5%, respectively. Most uncommon gliomas, including BRAF-driven tumors, could not be accurately classified just by NGS. These data indicate that, even in this era of advanced molecular diagnostics, histologic evaluation is still an essential part of optimal patient care., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

Spinocerebellar ataxia type 3 (SCA3), also known by the eponym Machado-Joseph disease, is an autosomal dominant CAG trinucleotide (polyglutamine) repeat disease that presents in young- to middle-aged adults. SCA3 was first described in Azorean individuals and has interesting epidemiological patterns. It is characterized clinically by progressive ataxia and neuropathologically by progressive degenerative changes in the spinal cord and cerebellum, along with degeneration of the cortex and basal ganglia. Here, we describe the clinical and neuropathologic features in a case of SCA3 with unique findings, including involvement of the inferior olivary nucleus and cerebellar Purkinje cell layer, which are classically spared in the disease. We also discuss research into the disease mechanisms of SCA3 and the potential for therapeutic intervention., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

Background: Progress in extending the survival of glioblastoma (GBM) patients has been slow. A better understanding of why patient survival remains poor is critical to developing new strategies. Postmortem studies on GBM can shed light on why patients are dying., Methods: The brains of 33 GBM patients were autopsied and examined for gross and microscopic abnormalities. Clinical-pathologic correlations were accomplished through detailed chart reviews. Data were compared with older published autopsy GBM studies that predated newer treatment strategies, such as more extensive surgical resection and adjuvant temozolomide., Results: In older GBM autopsy series, mass effect was observed in 72% of brains, with herniation in 50% of all cases. Infiltration of tumor into the brainstem was noted in only 21% of those older cases. In the current series, only 10 of 33 (30%) GBMs showed mass effect (P = 0.0003), and only 1 (3%) showed herniation (P < 0.0001). However, extensive GBM infiltration of the brainstem was present in 22 cases (67%, P < 0.0001), with accompanying destruction of the pons and white matter tracts. There was a direct correlation between longer median patient survival and the presence of brainstem infiltration (16.1 mo in brainstem-invaded cases vs 9.0 mo in cases lacking extensive brainstem involvement; P = 0.0003)., Conclusions: With improving care, severe mass effect appears to be less common in GBM patients today, whereas dissemination, including life-threatening brainstem invasion, is now more pronounced. This has major implications regarding preclinical GBM models, as well as the design of clinical trials aimed at further improving patient survival., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A subset of gliomas has DNA repair defects that lead to hypermutated genomes. While such tumors are resistant to alkylating chemotherapies, they may also express more mutant neoantigens on their cell surfaces, and thus be more responsive to immunotherapies. A fast, inexpensive method of screening for hypermutated gliomas would therefore be of great clinical value. Since immunohistochemistry (IHC) for the DNA mismatch repair (MMR) proteins Msh2, Msh6, Mlh1, and Pms2 is already used to screen for hypermutated colorectal cancers, we sought to determine whether that panel might have similar utility in gliomas. MMR IHC was scored in 100 WHO grade I-IV gliomas (from 96 patients) with known tumor mutation burden (TMB), while blinded to TMB data. Cases included 70 grade IV GBMs, 13 grade III astrocytomas, 4 grade II astrocytomas (3 diffuse astrocytomas and 1 pleomorphic xanthoastrocytoma), 1 grade I pilocytic astrocytoma, 2 grade III oligodendrogliomas, 7 grade II oligodendrogliomas, and 3 grade I glioneuronal tumors. Eight of 100 tumors showed loss of one or more MMR proteins by IHC, and all 8 were hypermutated. Among the remaining 92 gliomas with intact MMR IHC, only one was hypermutated; that tumor had an inactivating mutation in another DNA repair gene, ATM. Overall accuracy, sensitivity, and specificity for DNA MMR IHC compared to the gold standard of TMB were 99, 89, and 100%, respectively. The strongest correlates with hypermutation were prior TMZ treatment, MGMT promoter methylation, and IDH1 mutation. Among the 8 MMR-deficient hypermutated gliomas, 4 (50%) contained both MMR-lost and MMR-retained tumor cells. Together, these data suggest that MMR IHC could be a viable front-line screening test for gliomas in which immunotherapy is being considered. They also suggest that not all cells in a hypermutated glioma may actually be MMR-deficient, a finding that might need to be considered when treating such tumors with immunotherapies.

Pleomorphic xanthoastrocytoma (PXA) is a rare primary CNS tumor. Recent advances in the molecular characterization are helping to define subtypes of tumor. The discovery of BRAF mutations within a substantial percentage of PXA fosters a clearer understanding of the pathophysiology of these tumors with clear prognostic and therapeutic implications. These findings are expected to provide insight into the spectrum of clinical behavior observed in PXA, ranging from cure with surgery to diffuse dissemination throughout the neuraxis. This review details the clinical presentation including radiographic appearance of PXA. Pathology, including molecular pathology is discussed. Therapeutic management including surgical resection, radiotherapy and systemic therapies are reviewed.

The 195-amino-acid-long human Retinal Degeneration Protein 3 (RD3) is critical in the regulation of guanylate cyclase (GC) signaling and photoreceptor cell survival. Recently, we identified significant loss of RD3 in high-risk neuroblastoma and the influential role of RD3 in tumor progression. However, the functional characterization of RD3 in tumor systems has been hampered by the dearth of information on its localization in normal tissue and by the lack of antibodies suitable for staining FFPE tissue, primarily due to the inaccessibility of the epitopes. In this study, we validated a custom-synthesized RD3 antibody and investigated the expression/localization of RD3 in assorted human tissues. We observed stratified expression of RD3 in different cell types and subcellular location of retina. We demonstrated extensive positive RD3 immunoreactivity in various normal tissues and particularly strong dot-like perinuclear staining in the lining epithelial cells, suggesting that RD3 may play an important role in the normal functioning of epithelial cells. RD3 expression is limited in the CNS. While neuroblastoma is often RD3-positive, the adrenal medulla, where many neuroblastomas originate, is RD3-negative. Meta-analysis of RD3 transcriptional expression across normal tissues confirmed tissue-specific RD3 mRNA levels. Our results revealed the tissue-specific expression/localization profile of RD3 for the first time.

Objective: To determine the causes of neonatal deaths and their contributing factors., Material and Methods: We used the "three-delay model" to conduct an audit of the neonatal deaths that occurred between January 2006 and December 2010 at the Charles de Gaulle University Pediatric Hospital, in Ouagadougou., Results: The neonatal mortality rate was 12.3%. The main direct causes were infections (70%), cerebral distress (10%), respiratory distress (7%), congenital malformations (5.5%), prematurity (4.5%) and hemorrhagic syndromes (3%). All three delays were found: in decision making in 64.4% of cases, in access to health services in 77%, and in receiving appropriate care in 66.9%; they multiplied the risk of death by a factor of 4, 3 and 5, respectively., Conclusion: To reduce deaths of newborn babies, it is necessary to overcome the three delays that contribute to it, pending the improvement of socioeconomic conditions of populations. This combat requires optimizing the implementation of the subsidies for obstetric and neonatal emergency care and strengthening the involvement of all stakeholders, specifically, policy makers, the community and health professionals.

Introduction: The international community is increasing concerned about obesity, which it has become one of the most common noninfectious pandemics worldwide and affects a growing number of children., Material and Methods: We conducted an analytic cross-sectional study from May 25 to June 16, 2010, among a sample of 435 randomly selected students in secondary schools in the city of Ouagadougou to identify the factors contributing to obesity and overweight., Results: The main factors significantly associated with obesity and overweight were family history of obesity (OR = 7.4), higher socioeconomic level (OR =  3.8), snacking on candy (OR = 5, 3), pastry (OR = 3.5), and chocolate (OR = 12.6), frequent consumption of sweets (OR = 2.2), lack of physical activity (OR = 4.4), and conflictual family relationships (OR = 3.9)., Conclusion: Dealing with these factors in prevention activities should help to reduce the prevalence of overweight and obesity and their morbid consequences later on.

Purpose: To analyze the effects of radiotherapy (RT) and chemotherapy in relation to sensorineural hearing loss (SNHL) after contemporary treatment of nasopharyngeal carcinoma., Methods and Materials: A total of 87 nasopharyngeal carcinoma patients were treated with RT or chemoradiotherapy using either three-dimensional conformal RT or intensity-modulated RT between 2004 and 2005. Tympanometry and pure-tone audiogram assessments were performed before treatment and then serially at 6-month intervals. The dose-volume data of the cochlea were analyzed. The effects of cisplatin administered in concurrent and nonconcurrent phases was explored., Results: Of the 170 eligible ears, RT (n = 30) and chemoradiotherapy (n = 140) resulted in 40% (n = 12) and 56.4% (n = 79) persistent SNHL (> or = 15 dB loss), respectively, after a median follow-up of 2 years. SNHL at a high frequency was more frequent statistically in the chemoradiotherapy group than in the RT-alone group (55% vs. 33.3%, p < 0.01), but not at a low frequency (7.9% vs. 16.7%, p = 0.14). Within the chemoradiotherapy group, the mean cochlea dose and concurrent cisplatin dose were important determinants of high-frequency SNHL, with an odds ratio of 1.07/Gy increase (p = 0.01) and an odds ratio of 1.008/mg/m(2) increase (p < 0.01), respectively. Age, gender, and nonconcurrent cisplatin dose were not statistically significant factors. A mean radiation dose to the cochlea of <47 Gy would result in <15% of patients developing severe (> or = 30 dB) high-frequency SNHL., Conclusion: The results of our study have shown that high-frequency SNHL is significantly related to the mean cochlea dose and the concurrent cisplatin dose. A mean dose constraint of 47 Gy to the cochlea is recommended to minimize SNHL after chemoradiotherapy.

This study is the first study that provides useful guidelines to clinical microbiologists and technicians on the usefulness of full 16S rRNA sequencing, 5'-end 527-bp 16S rRNA sequencing and the existing MicroSeq full and 500 16S rDNA bacterial identification system (MicroSeq, Perkin-Elmer Applied Biosystems Division, Foster City, California, USA) databases for the identification of all existing medically important anaerobic bacteria. Full and 527-bp 16S rRNA sequencing are able to identify 52-63% of 130 Gram-positive anaerobic rods, 72-73% of 86 Gram-negative anaerobic rods and 78% of 23 anaerobic cocci. The existing MicroSeq databases are able to identify only 19-25% of 130 Gram-positive anaerobic rods, 38% of 86 Gram-negative anaerobic rods and 39% of 23 anaerobic cocci. These represent only 45-46% of those that should be confidently identified by full and 527-bp 16S rRNA sequencing. To improve the usefulness of MicroSeq, bacterial species that should be confidently identified by full and/or 527-bp 16S rRNA sequencing but not included in the existing MicroSeq databases should be included.

Barnidipine is a stereoselective single isomer formulation of a long-term acting dihydropyridine calcium antagonist (CaA). In anaesthetised animals, the antihypertensive response to barnidipine is accompanied by a diuretic effect. The aim of the present study was to examine whether barnidipine increased renal blood flow in a conscious animal model for essential hypertension. We compared the regional specific hemodynamic effects of barnidipine with those obtained with its racemic mixture and amlodipine. Male adult spontaneously hypertensive rats (SHR) were instrumented with Doppler flow probes and catheters to measure renal (RVR), mesenteric (MVR) and hindquarter (HQVR) vascular resistance changes. One week after surgery, barnidipine, its racemic mixture, and amlodipine were intravenously administered at three doses (n> or =10 per dose) causing comparable reductions in mean arterial pressure (MAP). At doses of 3, 10 and 30 microg/kg barnidipine reduced MAP (+/- SEM) by 8+/-2, 26+/-3 and 45+/-4 mmHg. Equipotent effects on MAP were achieved by the racemic mixture of barnidipine at 10, 30 and 100 microg/kg, and by amlodipine at doses of 100, 300 and 1000 microg/kg. Following the 3 microg/kg and 10 microg/kg dose, barnidipine reduced MVR (% +/- SEM) by 4+/-4 and 19+/-4, and RVR by 8+/-2 and 15+/-4, respectively. In contrast, HQVR remained unaltered. Similar data were obtained for the racemic mixture of barnidipine and for amlodipine, although for the latter the changes in RVR were half of those found after barnidipine. After the highest doses of barnidipine, its racemic mixture as well as amlodipine, HQVR fell more than 25% whereas RVR and MVR remained unaltered. Analysis of the dynamic response to the CaAs revealed that the reductions in vascular resistance were associated with decreased myogenic-like oscillations in blood flow. We conclude that, in conscious SHR, the single isomer barnidipine reduces MAP at doses which are three times lower than its racemic mixture and 30 times lower than amlodipine. In contrast to short-acting CaAs such as nifedipine and isradipine, which reduce mainly HQVR and do not reduce RVR (Nievelstein et al.; Eur J Pharmacol 113:187-198, 1985), the three long-term acting CaAs preferentially dilated the mesenteric and renal vascular bed. In view of the elevation of RVR in essential hypertension, the reduction of RVR may contribute to the long-term antihypertensive effects of barnidipine and amlodipine.

We observed 36 cases of pleuropulmonary staphylococcal infection (PPS) in infants aged 0 to 30 months, during a prospective study carried out between April 1st 1995 and March 31 1996 at the Pediatrics Department of Ouagadougou University Hospital. PPS accounted for 0.5% of all hospital admissions and 11.6% of all acute basal respiratory infections in children aged less than 30 months. Slightly more boys than girls were affected, with a sex ratio of 1.2. We identified the classic triad of symptoms: cough-fever-polypnea, associated with abdominal ballooning and a change in general condition. On X rays, the typical images showing parenchymatous bubbles were the second most frequent observation (27.8%) after parenchymatous opacities (69.5%). The most frequently used antibiotics were oxacillin (Bristopen), gentamycin (Gentallin) and cefuroxime-axetil (Zinnat). The prognosis of PPS is poor, with a high mortality rate (27.8%) and a risk of pleural recurrence. Being very young, late hospitalization, malnutrition and leukopenia were identified as factors indicating a poor prognosis. Recygling of health care personnel for the management of acute respiratory infections, a decrease in malnutrition and an improvement in vaccination cover are essential if the mortality and morbidity of acute respiratory infections, and PPS in particular, are to be reduced.

It is rather the rate of the vasodilator effect than its magnitude which determines the triggering of reflex tachycardia associated with dihydropyridine calcium antagonists (DHP-CA). We therefore compared the rate of the vasodilator effects of a series of CA (both DHP and non-DHP) in rat isolated mesenteric artery preparations (size 256 +/- 3 microns, length 2 mm) from male Wistar rats (weighing 300-350 g) in an isolated wire myograph according to Mulvany and Halpern [12]. The mean force of the KCl-induced contraction amounted to 2.3 +/- 0.1 mN/mm. Potency (given as IC50-values), differential time course of action and recovery of the contractile response of the vessels after wash-out were established. These three parameters adhere to the following sequences: (1. potency) barnidipine [corrected] > (S)-lercanidipine > barnidipine racemate [corrected]> amlodipine > nifedipine, lacidipine > (R)-lercanidipine > verapamil, mibefradil; (2. differential time course) lacidipine, amlodipine > (S)- and (R)-lercanidipine, barnidipine [corrected], barnidipine racemate [corrected] > mibefradil, verapamil, nifedipine; (3. recovery) nifedipine > verapamil, barnidipine [corrected], amlodipine > barnidipine, lacidipine > mibefradil, (R)-lercanidipine > (S)-lercanidipine. In conclusion, barnidipine [corrected] proved to be the most potent vasodilator agent; interestingly, barnidipine was 20 times less potent when applied as a racemic mixture. A slow onset of action in DHP is a very important mechanism in preventing reflex tachycardia. For non-DHP (verapamil, mibefradil) reflex tachycardia probably is prevented by a direct effect on the conductive tissue in the myocardium.

During the period of transmission of malaria, from August to November of 1993 and 1994, we conducted a study to determine the frequency of the clinical forms of severe and complicated malaria. The study involved children, from 6 months through 15 years old, admitted to the pediatric ward of the hospital in Ouagadougou, Burkina Faso. The criteria for inclusion followed the definition of severe malaria stated by the World Health Organization. We carefully noted the symptoms and signs on admission. Of the total of 719 children enrolled in the study, there was a prevalence of children under 5 years old. The most frequent clinical forms were those of coma (377 cases, 52.4%), prostration (268 cases, 37.3%), convulsion (152 cases, 21.4%), anemia (115 cases, 15.9%), and hypoglycemia (55 cases, 10.3%). No renal failure form was observed. We also observed the respiratory distress form (35 cases, 4.9%) and the hemorrhagic form (11 cases, 1.5%). Malaria remains a major cause of childhood morbidity and mortality in the developing world. Early therapeutic management of febrile attacks with chloroquine would reduce the incidence of severe and complicated malaria.

The aim of the present study was to evaluate the use of the noradrenaline analogue iodine-123 metaiodobenzylguanidine ([123I]MIBG) for the assessment of cardiac sympathetic activity in the presence of diabetes mellitus and/or hypertension in animal models. One model used Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) rendered diabetic at 12 weeks of age by an intravenous injection of streptozotocin (STZ). The other model used lean and obese Zucker rats. In all groups basic haemodynamic values were established and animals received an intravenous injection of 50 microCi [123I]MIBG. Initial myocardial uptake and wash-out rates of [123I]MIBG were measured scintigraphically during 4 h. After sacrifice, plasma noradrenaline and left cardiac ventricular beta-adrenoceptor density was determined. The diabetic state, both in STZ-treated rats (direct induction) and in obese Zucker rats (genetic induction), appeared to induce a lower cardiac density of beta-adrenoceptors, indicative of increased sympathetic activity. Cardiac [123I]MIBG then showed increased wash-outs, thereby confirming enhanced noradrenergic activity. This parallism of results led to the conclusion that [123I]MIBG wash-out measurements could provide an excellent tool to assess cardiac sympathetic activity non-invasively. However, in hypertension (WKY vs SHR), both parameters failed to show parallelism: no changes in beta-adrenoceptor density were found, whereas [123I]MIBG wash-out rate was increased. Thus, either [123I]MIBG washout or beta-adrenoceptor density may not be a reliable parameter under all circumstances to detect changes in the release of noradrenaline. Changes in the initial uptake of [123I]MIBG were observed as well. This may be a good marker for the disappearance of cardiac innervation, but it seems not to be a good parameter for distinguishing between loss of sympathetic innervation and enhanced uptake of noradrenaline in pathological conditions.

Since hypertensive disease and diabetes frequently occur simultaneously there exists a requirement for animal models where both pathological entities are combined. The streptozotocin (STZ)-spontaneously hypertensive rat (STZ-SHR) and the obese Zucker rat are examples of animal models where hypertension and diabetes occur simultaneously. STZ-SHRs develop a hyperglycaemic syndrome, associated with other biochemical and morphological changes that to some extent approach insulin-dependent diabetes mellitus (type 1 diabetes) combined with hypertension. The obese (Fa/?) Zucker rat is characterized by the simultaneous occurrence of obesity, hyperglycaemia, hyperinsulinaemia, hyperlipidaemia and moderate hypertension. As such it approaches the patient with non-insulin-dependent diabetes mellitus (type 2 diabetes) who is simultaneously hypertensive. Lean (fa/fa) Zucker rats are suitable controls with respect to the obese animals. Both animal models (STZ-SHRs and obese Zucker rats) were characterized with respect to their biochemical, morphometric and haemodynamic properties. Both models were examined in particular with respect to the pharmacological characteristics of their cardiovascular system, as discussed in the present survey.

Diabetes mellitus and hypertension are common chronic diseases that frequently occur simultaneously. The induction of streptozotocin (STZ) diabetes mellitus in spontaneously hypertensive rats (SHR) offers the opportunity to investigate the influence of both entities in a reproducible manner. We investigated the effects of various vasoconstrictors on isolated small arteries from the mesenteric vascular bed of normotensive rats (Wistar-Kyoto rats, WKY) and SHR with chronic (8 weeks), STZ-induced diabetes mellitus. No consistent changes in hemodynamic parameters of the (STZ-) normotensive and (STZ-) hypertensive rats were noted. The K(+)-normalization procedure yields the individual optimal lumen diameter, which was the same for the arteries of the four groups of rats. The passive wall tension resulting from this normalization procedure was higher only in preparations from the control hypertensive group as compared with those from the control normotensive rats. Morphological investigations showed that small arteries from control SHR had an increased tunica media thickness as compared with those of control WKY; the STZ-WKY had an increased tunica media thickness as compared with preparations from control WKY. The vasoconstriction caused by alpha 1-adrenoceptor stimulation [norepinephrine (NE), methoxamine] and serotonin is unchanged in chronic experimental diabetes. The diabetic state reduced the sensitivity [-log EC50(M)] for the concentration-response curves (CRC) of calcium chloride. The CRC of potassium chloride indicated the same sensitivities, but maximal active wall tensions of vessels from STZ-SHR were reduced as compared with those from STZ-WKY. The well-known enhancement of the effects of various contractile stimuli caused by hypertension could not be demonstrated for the isolated small arteries used in the present study, although a nonsignificant tendency was observed. However, the STZ-diabetic state did not cause important additional pharmacodynamic changes, despite the morphological alterations in those vessels.

The present study was undertaken to investigate the combined effects of hypertension and streptozotocin-induced diabetes mellitus in the rat. Accordingly, four groups of rats were studied: Wistar Kyoto rats (WKY), diabetic WKY, spontaneously hypertensive rats (SHR) and diabetic SHR, respectively. The mean arterial blood pressure was increased in hypertensive animals compared to normotensive animals. The base excess in the diabetic rats was higher than that of normoglycemic animals. An elevated glucose concentration was found in the blood and urine of streptozotocin-treated rats. Ketone bodies were detected in the urine and blood of the diabetic rats. Mortality rates after treatment were not different among the four groups. In separate experiments, isolated working hearts of the various groups were set up and analyzed. For the maximal left ventricular pressure (mm Hg) the following values were formed: 110.0 +/- 2.6, 93.6 +/- 2.7, 93.4 +/- 3.0, and 87.5 +/- 2.4, respectively. The wet heart weights, dry heart weights, and body weights of the diabetic rats were lower than those of normoglycemic animals. The wet heart weight/body weight ratio, however, was increased by diabetes and hypertension (0.43 +/- 0.01, 0.47 +/- 0.01, 0.47 +/- 0.01, and 0.54 +/- 0.02, respectively). There were no significant differences between the water content of the hearts from the four different groups. Pathologic examination of the hearts showed myocardial hypertrophy and medial hypertrophy of coronary arteries in diabetic and hypertensive animals. There was no difference in relative collagen content in the hearts of the four groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension and diabetes mellitus often co-exist and both conditions may be expected to cause synergistic vascular damage. Our group has introduced an animal model for simultaneously occurring hypertension and diabetes mellitus by treating spontaneously hypertensive rats with streptozotocin (STZ). We investigated the drug-induced endothelium-independent and -dependent relaxation in isolated mesenteric small arteries (resistance vessels). Concerning the influence of hypertension, the responses to sodium nitroprusside, methacholine, histamine and nifedipine proved unchanged, the vasodilator response to bradykinin was diminished, whereas that to the K(+)-channel opener cromakalim was enhanced. With respect to the influence of STZ-induced diabetes we found that the responses to sodium nitroprusside, methacholine and nifedipine were unchanged, and that to cromakalim was enhanced, also when the preparations were pretreated with glibenclamide. The responses to histamine (STZ WKY versus control WKY) and bradykinin (STZ SHR versus control SHR) proved enhanced in the isolated vessels taken from diabetic animals. These findings suggest that the influence of the diabetic state is more pronounced than that of hypertension. However, our findings do not indicate that either hypertension or diabetes is associated with generalised endothelial damage in the resistance arteries.

The diagnostic performance of three commercial assay kits [Phadezym RAST (PhRAST), Pharmacia CAP system (CAP), and multiple chemiluminescent assay (CLA-MAST)] for measuring serum-specific IgE was evaluated and compared using intradermal skin testing or skin prick testing as reference standards. Serum samples were obtained from allergic patients who were tested with either intradermal skin tests or skin prick tests (96 and 49 subjects, respectively). Six different allergen extracts were tested: Dermatophagoides pteronyssinus, Candida albicans, Aspergillus, short ragweed, Bermuda grass, and cockroach mix. Results showed that when using intradermal skin testing as a reference standard, the CLA-MAST had the lowest sensitivity (75%), specificity (80%), and efficiency (85%) but the Pharmacia CAP system achieved the highest sensitivity, specificity, and efficiency (86%, 94%, and 91%, respectively). When compared with these two relatively new assays, the Phadezym RAST had medium sensitivity (80%), specificity (92%), and efficiency (88%). In contrast, when using skin prick testing as a reference standard, the highest specificity was achieved by Phadezym RAST (95%), followed by Pharmacia CAP system (90%), and MAST (81%). As for the sensitivity of each test, the Phadezym RAST was the lowest (60%) and Pharmacia CAP system reached the highest sensitivity (79%); and for the efficiency test, the score was 87% for CAP, 83% for Phadezym RAST, and 75% for MAST. These results suggest, therefore, that the CAP system is the preferred test and provides a useful guide for prescription of environmental control and immunotherapy in unselected patients.

The present study was undertaken to evaluate the effects of R 56865 (N-[1-[4-(4-fluorophenoxy)-butyl]-4-piperidinyl)- N-methyl-2-benzothiazolamine) (Fig. 1) on postischemic ventricular function, an inhibitor of the Na+/Ca2+ overload, in the working heart preparation of the rat. The hearts were paced at 5 Hz and perfused with Tyrode solution of 37 degrees C at a physiological pH. After 15 min of pretreatment with R 56865, low-flow ischemia (30 min) was induced by reducing the perfusion pressure from 51.5 mmHg to 11.0 mmHg and R 56865 was infused simultaneously. The hemodynamic effects of R 56865 were evaluated in the concentration range [10(-8)-3.10(-6) M]. The five parameters measured were: LVP (Left Ventricular Pressure), +dP/dtmax (maximal rate of pressure increase), AO (Aortic Output), CF (Coronary Flow) and CO (Cardiac Output). They were determined in the working heart mode after 15 min of equilibration and at the end of the experiment. From these data the recovery percentages were calculated. The recovery percentages for the LVP, +dP/dtmax, AO, CF and CO for the control hearts (3.3%, 0.0%, 7.9%, 10.4% and 8.5%, respectively) differed significantly from those at 10(-7) M (39.6%, 40.8%, 25.0%, 41.8% and 29.9% respectively). The recovery percentage were the highest at 10(-6) M (79.6%, 82.1%, 54.7%, 92.7% and 67.2%, respectively). The concentration of 10(-7) M was associated with a smaller reduction in LVP (12.9%) than at 10(-6) M (25.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated the antiischemic effects of nifedipine in isolated working rat hearts from age-matched normotensive Wistar-Kyoto rats (WKY), diabetic WKY, spontaneously hypertensive rats (SHR), and diabetic SHR. Diabetes was induced by streptozotocin. First, we constructed concentration-response curves for the negative inotropic effect of nifedipine in every group. After 15 min of pretreatment with nifedipine (EC60), low-flow ischemia (30 min) was induced by reducing the afterload from 51.5 to 11.0 mm Hg and nifedipine was infused simultaneously. The six measured parameters were left ventricular pressure (LVP), maximum rate of pressure increase (+dP/dtmax), maximum rate of pressure decrease (-dP/dtmax), aortic output (AO), coronary flow (CF), and cardiac output (CO), determined after 15-min equilibration in the working heart mode and at the end of the experiment. From these data, the recovery percentages were calculated. There were no significant differences in sensitivity to nifedipine (as measured by the EC50 concentration) between the four groups with respect to LVP, +dP/dtmax, -dP/dtmax, CF, and CO. However, hearts from SHR were less sensitive to nifedipine than those from diabetic SHR and nondiabetic WKY with regard to AO. In isolated hearts from nondiabetic WKY and SHR, there were no significant differences between vehicle-treated organs and nifedipine-treated preparations. In hearts from diabetic WKY and diabetic SHR, however, the nifedipine-treated group (LVP 87.1 +/- 3.3 and 60.5 +/- 12.1%, respectively) recovered significantly (p < 0.05) better from ischemia as compared with the control group (LVP 35.7 +/- 14.7 and 10.7 +/- 9.8%, respectively) (n = 6 for each group).(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the influence of high-glucose levels (30.5 mmol/L) and/or hyperosmolarity on pharmacological responses in aortic ring preparations taken from nondiabetic rats. Moderate changes were observed for the concentration-response curves of noradrenaline and phenylephrine, but not for methoxamine and cirazoline. Maximal active forces of the concentration-response curves of potassium chloride and calcium chloride were significantly reduced by the elevated glucose levels per se, but neither the slopes of the curves nor the -logEC50 values were affected. Concentration-response curves of serotonin and U 46619 were not affected. For angiotensin II, the -logEC50 values and maximal active forces of the concentration-response curves were significantly lower under both hyperglycemic and hyperosmolar conditions. The present study suggests that potential changes in contractile behavior in isolated vessels from diabetic animals cannot be attributed to high glucose levels and/or hyperosmolarity as such, but indeed reflect vascular changes associated with the diabetic state. An exception has to be made for the depolarization of aortic ring preparations of nondiabetic rat; the elevated glucose level leads to an impaired calcium influx via the (slow) L-type calcium channels.

We have studied the effects of both hypertension and streptozotocin-induced diabetes mellitus on alpha 1-adrenoceptor mediated vasoconstriction, endothelium-dependent and endothelium-independent vasodilation. The experiments were performed in perfused mesenteric vascular bed preparations taken from age-matched SHR, WKY, diabetic SHR and diabetic WKY. For the alpha 1-adrenoceptor agonist methoxamine, the mesenteric preparations from SHR and diabetic SHR yielded significantly (p < 0.05) stronger maximal responses than preparations taken from WKY and diabetic WKY, respectively. The diabetic state significantly (p < 0.05) decreased the responsiveness to methoxamine in arteries from SHR and WKY. Hypertension does not significantly change the concentration response-curves for (acetyl-beta) methacholine, histamine, adenosine diphosphate and sodium-nitroprusside. However, the sensitivity to endothelium-dependent vasodilation decreased in preparations from diabetic animals (< 0.05). It is concluded that mesenteric resistance arteries from SHR and diabetic SHR are more reactive to alpha 1-adrenoceptor stimulation, whereas diabetes reduces the responsiveness to methoxamine in WKY and SHR. Hypertension does not affect the endothelium-dependent relaxation in mesenteric arteries. However, diabetes decreases the sensitivity to endothelium-dependent relaxation without altering the sensitivity to sodium-nitroprusside. These findings are indicative of a diabetes-induced endothelial dysfunction in mesenteric resistance arteries. In preparations from diabetic hypertensive rats the reduced response to methoxamine and the endothelial dysfunction seem to run parallel.