Apparent genotype–phenotype correlation in childhood,adolescent, and adult Chediak‐Higashi syndrome

Chediak‐Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, bleeding tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10–15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the CHS1 gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, we found only functionally null mutant CHS1 alleles, whereas in patients with the adolescent and adult forms of CHS we also found missense mutant alleles that likely encode CHS1 polypeptides with partial function. Together, these results suggest an allelic genotype–phenotype relationship among the various clinical forms of CHS. © 2002 Wiley‐Liss, Inc.     

The effects of blood osmolality changes on cat carotid body chemoreceptors in vivo

The possibility that carotid chemoreceptors respond to changes in plasma osmolality was investigated in the cat, perfusing the carotid artery with blood made hyper- or hypo-osmotic and recording chemoreceptor activity from carotid nerve fibers. Blood made hyperosmotic with sucrose or NaCl reduced the chemoreceptor discharge, while hypoosmotic blood increased chemoreceptor activity. The minimal osmolality variation necessary to obtain a detectable frequency change was 3–8% of the control. Frequency changes of 30% of the control were obtained with a 20% variation in osmolality. The frequency variations produced by the osmotic changes lasted as long as the infusion was maintained (up to 15 min). In some instances a rebound was observed when iso-osmotic saline was perfused again. A transient change in frequency and a clear rebound were obtained when blood made hyperosmotic with glycerol was perfused. These effects probably reflect a rapid change in intracellular osmolality due to the free passage of glycerol across cellular membranes.The modifications in chemoreceptor activity consecutive to osmolality variations are the opposite of those observed in isolated and superfused carotid bodies. As it is known that osmolality values affect the smooth muscle of the blood vessels, we conclude that our results are mainly produced by changes in carotid body blood flow due to a direct effect of hyper- and hypo-osmotic solutions on vascular muscle tone. Chemoreceptor excitation during a decrease in blood osmolality may contribute reflexly to the increased vascular resistance observed during acute osmolality reductions in man.     

Regeneration in grafts of normal and denervated rat muscles

Summary The soleus or extensor digitorum longus muscles of young rats were freely grafted into the bed of the corresponding contralateral muscle. The grafts were of normal muscle or muscles which had been denervated for 14 days. Grafts of normal muscle were characterized by little or no contractile activity for the first 2–4 days after transplantation. In contrast, denervated grafts contracted weakly, but consistently, throughout this early period. The patterns of contraction were complex. In early transplants, the contractions were due entirely to surviving muscle fibers in the graft, and the contractile characteristics were those of denervated muscle fibers. After the first week, contractions of newly regenerating muscle fibers within the grafts were superimposed upon and later took over those from the fibers that survived the original transplantation. The contraction time approached those of the normal soleus or extensor muscles during the second month after grafting, and the grafts contracted like fast or slow muscles.     

Asymmetric Infectivity of Pseudorecombinants of Cabbage Leaf Curl Virus and Squash Leaf Curl Virus: Implications for Bipartite Geminivirus Evolution and Movement

The bipartite geminiviruses squash leaf curl virus (SqLCV) and cabbage leaf curl virus (CLCV) have distinct host ranges. SqLCV infects a broad range of plants within the Cucurbitaceae, including pumpkin and squash, and CLCV has a broad host range within Brassicaceae that includes cabbage andArabidopsis thaliana.Despite this, the genomic A components of these viruses share a high degree of sequence identity, particularly in the gene encoding the replication protein AL1, and their common regions are 77% identical. However, there is unexpected sequence diversity in the common regions of the two CLCV genomic A and B components, these being only 80% identical. Based on these sequence similarities, we investigated the host range properties of pseudorecombinants of SqLCV and CLCV. We found that in a pseudorecombinant virus consisting of the A component of CLCV and the B component of SqLCV, both components replicated in tobacco protoplasts, and this pseudorecombinant was infectious and caused systemic disease inNicotiana benthamiana, a common host to all bipartite geminiviruses. However, this pseudorecombinant did not move systemically in pumpkin orArabidopsis, despite the demonstrated replication compatibility of the genome components. As a result of the greater sequence differences between the common regions, the pseudorecombinant of SqLCV A and CLCV B components neither replicated the CLCV B component nor systemically infected any of the hosts tested. These findings demonstrate that for different geminiviruses with distinct host ranges, the replication origins and AL1 proteins can be sufficiently similar to permit infectious pseudorecombinants, but replication alone is not sufficient to cause systemic disease, and host range may ultimately be limited at the level of movement. The results of this study further suggest that CLCV is an evolving virus that can provide insights into how new bipartite geminiviruses arise from mixed infections.     

Effect of interferon alpha,interferon beta,and interferon gamma on the in vitro growth of human renal adenocarcinoma cells

Interferon-, interferon-, and interferon- differ in their antiproliferative effects for several cell lines. Interferons were thus assessed for their activity in inhibiting proliferation of three renal cell carcinoma cell lines. The malignant epithelial phenotype of each of these cell lines was confirmed by electron microscopy, histology, karyotype and tumorigenicity. When compared on an anti-viral unit basis, naturally produced interferon- was more effective than natural interferon- for all cell lines and clones. Proliferation of each of the cell lines was inhibited by interferon-. In all cases, removal of interferons from culture media resulted in resumption of the rate of cell growth after a variable delay of 6–10 days. If the antiproliferative effects of interferons predominate in mediating tumor regression, clinical response may depend upon the type of interferon to which the tumor is exposed.     

Retinal oxygen tension and oxygen reactivity in retinopathy of prematurity in kittens

In the first series of experiments, preretinal oxygen tensions were measured using microelectrodes in newborn kittens, at 6 +/- 2 days of age, following their placement in an atmosphere of 80 to 90% oxygen for 5 +/- 1 day. The oxygen exposure caused an obliteration of the normally developing retinal vasculature. Preretinal oxygen tensions in the resultant avascular retina were close to zero while those in the vascular retina were near normal. The avascular retina was a "sink" for ocular oxygen. Oxygen breathing resulted in expected increases in preretinal oxygen tension, but, surprisingly, the preretinal oxygen tension decreased with continued oxygen administration. Because the oxygen tension in the avascular retinal area is determined primarily by the choroidal circulation, we speculated that increased oxygen caused a decreased choroidal blood flow. In the second series of experiments, however, choroidal blood flow was measured in the kittens by applying a temperature probe to the sclera and oxygen breathing did not appear to have an effect. These results did not support the initial speculation. It may be that the decrease in preretinal oxygen tension observed with continued oxygen administration resulted from progressive increase in utilization.     

High Case-Fatality Rate for Human Anthrax,Northern Ghana, 2005–2016

The human cutaneous anthrax case-fatality rate is ≈1% when treated, 5%–20% when untreated. We report high case-fatality rates (median 35.0%; 95% CI 21.1%–66.7%) during 2005–2016 linked to livestock handling in northern Ghana, where veterinary resources are limited. Livestock vaccination and access to human treatment should be evaluated.     

Opisthotonos following propofol: A nonepileptic perspective and treatment strategy

In this report of opisthotonos during recovery from propofol anaesthesia, we relate clinical observations with scientific considerations, and propose a strategy for treatment of this rare side effect. Following a brief operative procedure, a healthy 29-yr-old woman developed recurrent opisthotonos while recovering from anaesthesia with alfentanil, propofol, and nitrous oxide. In contrast to accumulating reports, the patient remained conscious during each episode of back extension and retrocollis. The preservation of consciousness and similarities to strychnine-induced opisthotonos suggest to us that the mechanism may have a brainstem and spinal origin. Recent investigations show that propofol potentiates the inhibitory transmitters glycine and γ-aminobutyric acid (GABA) which would enhance spinal inhibition during anaesthesia. Postanaesthetic opisthotonos, however, may be due to a propofol-induced tolerance to inhibitory transmitters. This rebound phenomenon would lead to an acute, enduring refractoriness in inhibitory pathways of the brainstem and spinal cord, resulting in increased activity of extensor motoneurons. We recommend a therapeutic strategy that restores inhibition by glycine and GABA at multiple sites; the preferred therapeutic agents would be diazepam and physostigmine. The episodes are usually short-lived, but two of the reviewed 17 patients developed recurrent retrocollis for four and 23 days following antiepileptic drug therapy. Since high doses of phenytoin and carbamazepine can result in opisthotonos, we recommend that anticonvulsants be reserved for post-anaesthetic patients with electroencephalographic evidence of seizure activity.     

Limitations in the use of tubulin polymerization assays as a screen for the identification of new antimitotic agents: The potent marine natural product curacin A as an example

Curacin A is a newly isolated lipid natural product that binds in the colchicine site of tubulin and inhibits mitosis. We have examined its effects on tubulin polymerization, studied by turbidimetry, under three reaction conditions. In 1.0 M glutamate + 1.0 mM MgCl₂, with a 37°C reaction temperature, we could find no concentration of curacin A that completely inhibited polymerization. A maximal inhibitory effect on turbidity development (about 50%) was observed with 5 m?M drug. Higher drug concentrations induced an abnormal polymerization reaction, which at 40 m?M differed little from the control reaction except for slightly delayed depolymerization in response to reducing the temperature to 0°C. In 0.8 M glutamate (no MgCl₂), with a 30°C reaction temperature, complete inhibition did occur at 3–5 m?M drug, but higher drug concentrations again induced an abnormal polymerization reaction. With 40 m?M curacin A this reaction was also similar to the control reaction, except that cold-induced depolymerization was slightly enhanced relative to the control. When polymerization was induced by microtubule-associated proteins, maximal inhibition of turbidity development (about 70%) occurred with 2 m?M drug, with higher curacin A concentrations inducing abnormal polymerization reactions that reached about 60% of the control turbidity readings. Under all three reaction conditions the polymer induced by high concentrations of curacin A consisted of large aggregates of tightly coiled spiral fibers that had a 2–3 filament substructure. The implications of these findings with curacin A are discussed in terms of the use of tubulin polymerization assays as a screen for identifying new antimitotic drugs. © 1995 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Positron Emission Tomography in Grading Soft Tissue Sarcomas

Soft tissue sarcomas present with varied radiological appearances. Positron imaging with [F-18] fluorodeoxyglucose (FDG PET) has recently made promising contributions to management of patients by providing a noninvasive means for evaluating tumor metabolism and providing important biological information about soft tissue malignant tumors. PET imaging not only gives quantitative data on metabolic rates of tumors but can also readily provide semiquantitative data of uptake of tumors by measuring uptake ratios. These values have been helpful for noninvasively grading tumors. This value is called the tumor standard uptake value (SUV). The tumor grades (low, intermediate, high) mean SUV values show a high level of significance in discrimination among tumor grade groups.