Central nervous system multiple myeloma – potential roles for intrathecal therapy and measurement of cerebrospinal fluid light chains

Central nervous system (CNS) multiple myeloma (MM) is exceedingly rare and portends a dismal prognosis. While immunomodulators have contributed to the improvement in survival in MM, they appear to have limited activity against CNS MM and, paradoxically, may contribute to the evolution of resistant MM clones capable of surviving within the CNS. We undertook a retrospective analysis to characterize the features of CNS MM and outcome in 17 patients from four institutions identified between 2000 and 2011. The median age was 58 years. Patients had received a median of three prior therapies and all had been exposed to at least one of the so‐called novel anti‐MM agents before the diagnosis of CNS MM. The median time to CNS disease from initial diagnosis was 36 months. Cerebrospinal fluid (CSF) light chain measurements produced discrepant results to serum light chain measurements in some patients. Treatments included systemic pharmacotherapy, intrathecal (IT) chemotherapy and/or radiotherapy (RT). The median overall survival (OS) from diagnosis of CNS MM was only 4 months. OS was significantly better in patients who received IT chemotherapy (20 months vs. 2 months, respectively; P < 0·02). We conclude that the systematic evaluation of IT therapy and diagnostic utility of CSF light chain measurements in CNS MM are warranted.     

The Small-Intestinal Mucosa in Patients with Crohn's Disease Assessed by Scanning Electron and Light Microscopy

Small-intestinal mucosal biopsy specimens obtained by a Watson capsule were, assessed by light (LM) and scanning electron (SEM) microscopy in 18 patients with various sites of Crohn's disease and in 6 healthy controls. By means of LM. partial villous atrophy of the upper small-intestinal mucosa was assessed in six patients. With the use of SEM a further seven patients were shown to have mucosal abnormalities of possible clinical significance. These specimens showed a convoluted villous pattern at low-power SEM and some also enterocyte irregularity, bulging, and surface ultrastructural distortion at medium- and high-power SEM. The medium- and high-power mucosal alterations were unevenly distributed. The high prevalence of abnormalities of the upper small-intestinal mucosa in patients with Crohn's disease elsewhere in the gastrointestinal tract adds further weight to the concept of a diffuse involvement along the entire gastrointestinal tract in Crohn's disease.     

Poor agreement between light transmission aggregometry,Verify Now P2Y12 and vasodilatator-stimulated phosphoprotein for clopidogrel low-response assessment: A potential explanation of negative results of recent randomized trials

Abstract

Clopidogrel low response as assessed by several different biological tests correlates with poor prognosis after percutaneous coronary intervention (PCI). However, recent randomized clinical trials (RCT) testing the strategy of individual antiplatelet therapy tailoring based on one sole test have all shown negative results. Poor correlation between the different tests may explain the difficulties of patient selection and identification of “true poor responders” to clopidogrel. In this prospective study, clopidogrel response was assessed in 100 consecutive patients between 18 and 24 hours after a 600?mg clopidogrel loading dose using three different tests: light transmission aggregometry with 10?μmol ADP (LTA, results expressed as platelet aggregation percentage: PAP), Verify Now P2Y₁₂ (VN, results expressed as P2Y₁₂ reaction unit: PRU) and vasodilatator-stimulated phosphoprotein (VASP, results expressed as platelet reactivity index: PRI). Patients under chronic clopidogrel therapy were excluded. The mean PAP, PRU and PRI values were 38.6%, 176.1 PRU and 52.4%, respectively. When clopidogrel response was analyzed as continuous variable, there was a good correlation between the different tests: LTA/VN (R^2?=?0.642, p?<?0.001), LTA/VASP (R^2?=?0.409, p?<?0.001) and VN/VASP (R^2?=?0.616, p?<?0.001). However, when clopidogrel response was analyzed as pre-specified cut-off points to define patients as “poor or good responders” (according to the literature: 50% PAP for LTA, 235 PRU for VN and 50% PRI for VASP), only 47% of the patients were defined as “good” or “poor responders” by the three tests. Altogether, 33% of the patients were defined as “poor responders” by only one test, 20% by two tests and only 16% by the three tests. The correlation between the different tests is good when clopidogrel response is analyzed as continuous variable. Each individual is however rarely (less than 50%) defined as “poor or good responder” by all the three tests when pre-specified cut-off values are used. A sole test might not be sufficient to manage antiplatelet therapy in an individual patient and these results may explain the results of recent RCT showing the lack of benefit of systematic antiplatelet therapy monitoring strategy.     

Evolutionary comparison of the avian IgL locus: combinatorial diversity plays a role in the generation of the antibody repertoire in some avian species

Immunoglobulin light chain (IgL) diversity is generated in the chicken by recombination between the single functional variable (VL) and joining (JL) gene segments and subsequent somatic diversification of the rearranged VL region. In order to determine whether these events are a general feature of avian IgL genes, we analyzed the organization and recombinatorial characteristics of the IgL loci of several other avian species. Southern blot analysis of bursal and germline DNA using chicken VL and constant (CL) probes revealed that the IgL loci of quail, mallard duck, pigeon, turkey, cormorant, and hawk consist of a family of VL elements, but undergo a single major rearrangement event similar to that observed in chickens. In contrast, several rearrangements were observed in the Muscovy duck locus. A phage clone containing a 26 kb insert that hybridized to VL and CL probes was isolated from a Muscovy duck erythrocyte DNA genomic library. Nucleotide sequencing revealed that the clone contained a single JL-CL region flanked on the 5' side by five VL segments. Unlike the chicken, two of the VL segments (VL1, VL5) appear to be functional. The remaining three VL segments are pseudogenes that lack promoter and leader sequences, but one of these (psi VL3) has recombination signal sequences. Overall, these data indicate that rearrangement of one VL gene segment is a general feature of the IgL locus in many avian species. In these species, the presence of a family of VL elements that do not rearrange suggests that a pseudogene pool may be available for somatic diversification by gene conversion. The organization of the Muscovy duck IgL locus suggests that additional combinatiorial diversity has evolved independently in some avian species.     

Effect of beta-globin gene cluster haplotype on the hematological and clinical features of sickle cell anemia

In 113 black American adults with sickle cell anemia (HbSS), we examined nine polymorphic restriction sites, including the Xmnl site 5' to the G gamma gene, to see whether haplotype is related to the level of HbF and the proportion of G gamma chains or if it influences the hematological and clinical features of the disease. Seventy-five percent of the patients were homozygous or heterozygous for the Benin (no. 19) or Central African Republic (Bantu, no. 20) haplotypes; 13.3% were homozygous or heterozygous for the Senegal (no. 3) haplotype, while 11.5% had other genotypes. Of the subjects, 14.2% were either homozygous or heterozygous for the Xmnl restriction site 5' to the G gamma gene. We found no effect of haplotype on HbF levels. The level of G gamma chains was 60.5% +/- 17.0% in individuals heterozygous or homozygous for haplotype no. 3 and was 46.9% +/- 11.6% in individuals with other haplotypes. Subjects with the Xmnl site 5' to the G gamma gene had G gamma globin levels of 59.5% +/- 16.7% while those lacking that site had an average of 47.2% +/- 12.1%. There were no significant differences among these groups in hemoglobin concentration, packed cell volume, mean cell volume, or clinical indicators of vaso-occlusive severity, including crises, hospitalizations per year, aseptic bone necrosis, acute chest syndrome, or leg ulcers. While the presence of haplotype 3 and the 5' G gamma Xmnl site were associated with increased G gamma chains, there was no effect on HbF level or other hematological and clinical features that might reflect disease severity. It is likely that determinants unrelated to haplotype, linked or unlinked to the beta-globin gene cluster, are the major effectors of differences in the levels of HbF in American patients with sickle cell anemia.     

裂隙灯致视网膜损伤的病理学观察

作者用国产裂隙灯对1只恒河猴双眼黄斑周围视网膜8个部位进行随机持续光照。视网膜照度为226.8mW/cm~2。照射时间分别为105,150min。通过光镜、电镜对光照后即刻到1mo的病灶区视网膜进行观察。光照性视网膜病变主要表现为光感受器和RPE细胞损害,脉络膜血管有大量白细胞渗出。裂隙灯致视网膜损伤主要是光化学反应造成,同时有光凝及炎症反应参与。并提出节省动物和实验时间,避免个体差异的多部位病理取材方法。     

A Quantitative Visualization Study of Flow in a Scaled-up Model of a Centrifugal Blood Pump

Abstract: A quantitative flow visualization study of a scaled-up model of a centrifugal blood pump was performed. Since the size of the scaled-up model was three times as large as the original pump under development, and the kinematic viscosity of the saline solution used as the working fluid was approximately one-third that of the blood, we obtained a similar flow at one twenty-seventh the angular velocity of the original pump. The flow was visualized by seeding the saline solution with neutrally buoyant particles and by illuminating the model with a laser light sheet. Since the gap flow behind the impeller is important for thrombus formation, it was recorded by a high-speed video camera, and the velocity field was evaluated automatically by particle tracking velocimetry. It was shown that in the gap behind the impeller there existed a region where the velocity profile was almost flat which can be called a core region. The results indicated the effectiveness of the present visualization technique for centrifugal blood pumps.     

Ultrastructural evidence for a paucity of projections from the lumbosacral cord to the pontine micturition center or M-region in the cat: A new concept for the organization of the micturition reflex with the periaqueductal gray as central relay

Information concerning the rate of bladder filling is determined by receptors in the bladder wall and conveyed via afferent fibers in the pelvic nerve to sensory neurons in the lumbosacral cord. It was assumed that this information is relayed from the lumbosacral cord to a medial cell group in the dorsolateral pontine tegmentum, called the M-region, the pontine micturition center, or Barrington's nucleus. The M-region, in turn, projects via long descending pathways to the sacral parasympathetic motoneurons. In the present electron microscopic study, it was investigated in cats whether monosynaptic projections from lumbosacral neurons to the M-region indeed exist. Wheat-germ agglutinin-horseradish peroxidase injections were made into the lumbosacral cord. Many retrogradely labeled dendrites and somata were found in the M-region, but no labeled terminals were found on retrogradely labeled dendrites or somata. Only a small number of anterogradely labeled terminals, which were filled with mainly round vesicles, contacted unlabeled dendrites in the M-region. In contrast, many more anterogradely labeled terminals, which were filled with mainly round and, to a limited extent, dense core vesicles and with asymmetrical synapses, were found on dendrites in the lateral part of the periaqueductal gray (PAG). Previously (Blok and Holstege [1994] Neurosci. Lett. 166:93–96), it was demonstrated that the lateral part of the PAG contains neurons projecting to the M-region. A concept for the central organization of the micturition reflex is presented in which ascending projections from the lumbosacral cord convey information on bladder filling to the PAG. When the bladder contains so much urine that voiding is necessary, the PAG, in turn, triggers the M-region. The M-region, however, also receives afferents from the preoptic area, which might be involved in phe final decision to start micturition. © 1995 Wiley-Liss, Inc.