Prominent Orcadian Absorption of Intranasal Salmon Calcitonin (SCT) in Healthy Subjects

In young healthy subjects salmon calcitonin (SCT), intranasally administered, increased in serum as a function of the drug administration time. The serum concentration of a 400 IU SCT dose monitored 10 min after dosing was statistically more significant when inhaled at 0000 than at other, more conventional, administration times (morning or evening). Following dosing at certain times during the day, the serum SCT was less or even questionable with the dose and under the study conditions selected. Dosing without consideration of timing may lead to reduced effect or lack of effect or perhaps ambiguity or controversy regarding the possible circumstance of a “non-absorbent subject”. The circadian frequency appears to be a critical determinant of intranasal SCT absorption suggesting administration time to be an important factor in the cost/benefit ratio without the unpleasant side effects sometimes experienced through parenteral routes.     

Prominent Orcadian Absorption of Intranasal Salmon Calcitonin (SCT) in Healthy Subjects

In young healthy subjects salmon calcitonin (SCT), intranasally administered, increased in serum as a function of the drug administration time. The serum concentration of a 400 IU SCT dose monitored 10 min after dosing was statistically more significant when inhaled at 0000 than at other, more conventional, administration times (morning or evening). Following dosing at certain times during the day, the serum SCT was less or even questionable with the dose and under the study conditions selected. Dosing without consideration of timing may lead to reduced effect or lack of effect or perhaps ambiguity or controversy regarding the possible circumstance of a “non-absorbent subject”. The circadian frequency appears to be a critical determinant of intranasal SCT absorption suggesting administration time to be an important factor in the cost/benefit ratio without the unpleasant side effects sometimes experienced through parenteral routes.     

Dynamics of bone marrow changes in patients with chronic idiopathic myelofibrosis following allogeneic stem cell transplantation

Scant knowledge exists about the dynamics of fibro-osteosclerotic bone marrow (BM) lesions and regeneration of hematopoiesis following allogeneic peripheral stem cell transplantation (SCT) in chronic idiopathic myelofibrosis. Therefore, an immunohistochemical and morphometric study was performed on BM biopsies in 20 patients before and at standardized intervals (days 30 through 384) following SCT. In responding patients, a total regression of the pretransplant increased fibrosis was completed in the posttransplant period after about six months, while the extent of osteosclerosis did not change significantly during observation time. The quantity of CD61+ megakaryocytes including precursors was strikingly variable after SCT and, by using planimetric methods, atypical microforms exhibiting a dysplastic aspect could be demonstrated. These anomalies may be responsible for posttransplant thrombocytopenia. CD34+ progenitor cells were increased before transplantation, however, their number declined rapidly to normal values in responding patients. Nucleated erythroid precursors revealed a decreased amount before and after SCT accounting for anemia. Large clusters of this cell lineage indicated an initial hematopoietic reconstitution comparable with the expansion of the neutrophil granulopoiesis. Proliferative activity and apoptosis showed an increase until one year after SCT that implied a still regenerating hematopoiesis in keeping with an enhanced cell turnover.     

Effect of calcitonin on the prolactin surge of proestrus

The effect of calcitonin (CT) on the prolactin (PRL) surge of proestrus in rats was investigated under normal and perturbed lighting conditions. Salmon calcitonin (SCT) was injected i.p. on diestrus 2 or on proestrus, plasma PRL levels were measured by radioimmunoassay. SCT had no effect on the PRL surge under normal lighting conditions but it induced a small drop in PRL level measured on proestrus morning, 3 hours after CT injection. Animals submitted to perturbed light conditions had higher PRL levels than those kept under normal lighting. These data would indicate that for the female rats on proestrus the sensitivity to stress due to injection and blood sampling may be modulated by changing the photoperiod. SCT injection under these conditions may facilitate this destabilization in PRL level.     

Use of naloxone challenge to predict sexual performance of rams before the fall breeding season

Serving capacity tests (SCT) identify rams as sexually active, sexually inactive, or low sexual performers. Labor and time requirements make SCT impractical and expensive. Therefore, a hormone-based test for libido was developed using the responses of LH and testosterone (T) after naloxone. This test effectively identified sexually active and inactive rams during the breeding season (November and December). The current study evaluated the effectiveness of this method at a different time of the year. Objectives were to determine if the blood test can detect differences in libido during late July and August, and to characterize LH and T profiles up to 120 min postnaloxone treatments at this time of year. Two experiments were conducted using i.v. naloxone at 0.75 mg/kg BW. Sexually active (SA) and sexually inactive (SIA) rams were identified using SCT. In Experiment 1, 16 SA and 18 SIA rams of several breeds were identified based on SCT conducted before naloxone tests. In Experiment 2, 72 Suffolk x white face rams were given SCT after naloxone tests and were of unknown sexual activity at the time of the naloxone tests. Mixed model analyses for repeated measures with repeated factors (month and sample time) and a covariate for mean LH or T before naloxone treatment were used for LH and T data. Proc Logistics modeled probabilities that rams were sexually active. The LH response to naloxone increased but did not differ (P > 0.09) by ram class (SA or SIA) or month. The T response peaked 75-90 min after naloxone treatment and was still elevated at 120 min. Testosterone differed (P < 0.03) for ram class by month by time in Experiment I and differed (P < 0.01) between months in Experiment 2. Proc Logistics incorrectly indicated that SA and SIA rams were all sexually active. This study indicates that the naloxone challenge test cannot discriminate between SA and SIA rams during July and August. Further research is required to determine the time of year when this sire identification test for libido has significant accuracy.     

Transplantation of hematopoietic stem cells from the peripheral blood

Hematopoietic stem cells can be collected from the peripheral blood. These hematopoietic stem cells (HSC), or better progenitor cells, are mostly expressed as the percentage of cells than react with CD34 antibodies or that form colonies in semi-solid medium (CFU-GM). Under steady-state conditions the number of HSC is much lower in peripheral blood than in bone marrow. Mobilization with chemotherapy and/or growth factors may lead to a concentration of HSC in the peripheral blood that equals or exceeds the concentration in bone marrow. Transplantation of HSC from the peripheral blood results in faster hematologic recovery than HSC from bone marrow. This decreases the risk of infection and the need for blood-product support. For autologous stem-cell transplantation (SCT), the use of peripheral blood cells has completely replaced the use of bone marrow. For allogeneic SCT, on the other hand, the situation is more complex. Since peripheral blood contains more T-lymphocytes than bone marow, the use of HSC from the peripheral blood increases the risk of graft-versus-host disease after allogeneic SCT. For patients with goodrisk leukemia, bone marrow is still preferred, but for patients with high-risk disease, peripheral blood SCT has become the therapy of choice.     

Recent approaches in acute lymphoblastic leukemia in adults

In the last decades outcome of adult acute lymphoblastic leukemia (ALL) has improved considerably. In large multicenter studies remission rates range from 75% to 89%, and long-term leukemia-free survival (LFS) from 28% to 39%. Major progress has also been made regarding better characterization of subtypes of ALL. Complete diagnostic procedures are essential to identify these subtypes which have significant differences in clinical and laboratory features and prognosis. LFS of > 50% can be expected in favorable subtypes such as T-ALL or mature B-ALL, while LFS of < 20% is expected in Ph/BCR-ABL positive ALL. Prognostic factors can be used for risk stratification and selection of treatment strategies can be adapted to the subtype and relapse risk. This includes measurement of minimal residual disease (MRD) to evaluate individualized treatment strategies adapted to the molecular response. Several new approaches for improvement in chemotherapy and stem cell transplantation (SCT) are under investigation. They include the use of intensified anthracyclines, asparaginase, cyclophosphamide or high-dose cytarabine during induction and intensive rotational chemotherapy during consolidation. Also SCT - mainly from sibling donors - is now part of standard treatment of de novo ALL, although it remains open whether indications should be based on prognostic factors or whether SCT should be offered to all patients with sibling donor. However, substantial progress can only be achieved by new, experimental strategies. These include new approaches for SCT, such as nonmyeloablative SCT, measurement of MRD, causal treatment with molecular targeting, e.g. with kinase inhibitors, and antibody therapy.     

Capacity for differentiation and normalization of populations of tumor cells transplanted into the anterior chamber of the eye. I. Changes in the pleomorphic rhabdomyosarcomas MKh-III and A-7 of mice

Tumors transplanted into the eye anterior chamber (EAC) were atypic, more differentiated morphologically and with higher activity of H-forms of LDH, compared to the same tumors grown in the subcutaneous connective tissue (SCT). Besides, in the EAC, the tumors were less karyotypically heterogeneous and had lesser mitotic indices, than in the SCT. After cultivation in the EAC, populations of tumor rhabdomyoblasts displayed a decreased transplantability in SCT, i.e. the usual site of their implantation. These results may suggest that the proliferation of tumor cell populations in the EAC, i.e. in the immunologically privileged place, can be accompanied by the reducing of their malignancy up to the total loss of the common tumorigenic ability. Even the cell populations of tumor rhabdomyoblasts from the late stages of tumor progression can undergo such a process of normalization.     

Regulation of cytoplasmic pH of cultured bovine corneal endothelial cells in the absence and presence of bicarbonate

Summary Single sodium-channel currents were measured in neuroblastoma cells after inhibition of inactivation by chloramine-T (CHL-T), sea anemone toxin II (ATX-II) and scorpion toxin (SCT). The decaying phase of the averaged single-channel currents recorded with 90-msec pulses in cell-attached patches was clearly slower than that of the unmodified channels, suggesting inhibition of macroscopic inactivation. Each substance caused repetitive openings and a moderate increase in the channel open time. AtV _m =RP+20 mV andT=12°C, the mean channel open times were 1.4, 1.6 and 1.8 msec for CHL-T, ATX-II and SCT, respectively, as opposed to 1.07 msec for native channels. Open-time histograms could be best fitted by the sum of two exponentials. The time constants of the fits were similar for histograms constructed from single openings and from openings during bursts. This suggests that the population of channels is homogeneous and that in bursts the same open conformations of channels occur as in single openings. Mean burst durations for bursts consisting of more than one opening atV _m =RP+20 mV were 4.9, 5.8 and 6.1 msec for CHL-T, ATX-II and SCT, respectively. Burst open-time histograms constructed from two or three openings were fitted by the gamma function. The different time constants of the fits obtained for ATX-II and SCT suggested multiple open conformations of channels for openings of bursts. However, significantly different open-time histograms constructed from the first, second and third openings of bursts could not be obtained systematically. A positive correlation was found for the dwell time of the first and the second, as well as for the second and the third opening of bursts with each substance, but a negative one for the dwell time of an opening and the neighboring closing of bursts with ATX-II. The results suggest a model with multiple open and inactivated states. In this model the inactivated states are weakly absorbing.     

The spinocervical tract as a possible pathway for muscular nociception.

In decerebrate and chloralose-anaesthetized spinal cats, micro-electrode recordings were made from axons of the spinocervical tract (SCT) during intra-arterial injection of bradykinin, 5-hydroxytryptamine and potassium into the gastrocnemius-soleus (GS) muscle. The results suggest that muscular group IV and group III afferent units which respond to the above painful stimulation project into the SCT. The portion of SCT units that could be activated by injections of these algesic substances into the GS-muscle was different in spinal and decerebrate preparations, showing that the SCT neurones are subject to a descending influence. It is concluded that the spinocervical tract, in addition to its function as a cutaneous sensory pathway, may serve as a pathway for muscular nociception in the cat.     

Chromosome-scale genomes reveal genomic consequences of inbreeding in the South China tiger: A comparative study with the Amur tiger

The South China tiger (Panthera tigris amoyensis, SCT) is the most critically endangered subspecies of tiger due to functional extinction in the wild. Inbreeding depression is observed among the captive population descended from six wild ancestors, resulting in high juvenile mortality and low reproduction. We assembled and characterized the first SCT genome and an improved Amur tiger (P. t. altaica, AT) genome named AmyTig1.0 and PanTig2.0. The two genomes are the most continuous and comprehensive among any tiger genomes yet reported at the chromosomal level. By using the two genomes and resequencing data of 15 SCT and 13 AT individuals, we investigated the genomic signature of inbreeding depression of the SCT. The results indicated that the effective population size of SCT experienced three phases of decline, ~5.0–1.0 thousand years ago, 100 years ago, and since captive breeding in 1963. We found 43 long runs of homozygosity fragments that were shared by all individuals in the SCT population and covered a total length of 20.63% in the SCT genome. We also detected a large proportion of identical-by-descent segments across the genome in the SCT population, especially on ChrB4. Deleterious nonsynonymous single nucleotide polymorphic sites and loss-of-function mutations were found across genomes with extensive potential influences, despite a proportion of these loads having been purged by inbreeding depression. Our research provides an invaluable resource for the formulation of genetic management policies for the South China tiger such as developing genome-based breeding and genetic rescue strategy.     

A Monte Carlo software bench for simulation of spectral k-edge CT imaging: Initial results

PurposeSpectral Computed Tomography (SCT) systems equipped with photon counting detectors (PCD) are clinically desired, since such systems provide not only additional diagnostic information but also radiation dose reductions by a factor of two or more. The current unavailability of clinical PCDs makes a simulation of such systems necessary.MethodsIn this paper, we present a Monte Carlo-based simulation of a SCT equipped with a PCD. The aim of this development is to facilitate research on potential clinical applications. Our MC simulator takes into account scattering interactions within the scanned object and has the ability to simulate scans with and without scatter and a wide variety of imaging parameters. To demonstrate the usefulness of such a MC simulator for development of SCT applications, a phantom with contrast targets covering a wide range of clinically significant iodine concentrations is simulated. With those simulations the impact of scatter and exposure on image quality and material decomposition results is investigated.ResultsOur results illustrate that scatter radiation plays a significant role in visual as well as quantitative results. Scatter radiation can reduce the accuracy of contrast agent concentration by up to 15%.ConclusionsWe present a reliable and robust software bench for simulation of SCTs equipped with PCDs.     

BDNF Overexpression Exhibited Bilateral Effect on Neural Behavior in SCT Mice Associated with AKT Signal Pathway

Spinal cord injury (SCI), a severe health problem in worldwide, was commonly associated with functional disability and reduced quality of life. As the expression of brain-derived neurotrophic factor (BDNF) was substantial event in injured spinal cord, we hypothesized whether BDNF-overexpression could be in favor of the recovery of both sensory function and hindlimb function after SCI. By using BDNF-overexpression transgene mice [CMV-BDNF 26 (CB26) mice] we assessed the role of BDNF on the recovery of neurological behavior in spinal cord transection (SCT) model. BMS score and tail-flick test was performed to evaluate locomotor function and sensory function, respectively. Immunohistochemistry was employed to detect the location and the expression of BDNF, NeuN, 5-HT, GAP-43, GFAP as well as CGRP, and the level of p-AKT and AKT were examined through western blot analysis. BDNF overexpressing resulted in significant locomotor functional recovery from 21 to 28 days after SCT, compared with wild type (WT)+SCT group. Meanwhile, the NeuN, 5-HT and GAP-43 positive cells were markedly increased in ventral horn in BDNF overexpression animals, compared with WT mice with SCT. Moreover, the crucial molecular signal, p-AKT/AKT has been largely up-regulated, which is consistent with the improvement of locomotor function. However, in this study, thermal hyperpathia encountered in sham (CB26) group and WT+SCT mice and further aggravated in CB26 mice after SCT. Also, following SCT, the significant augment of positive-GFAP astrocytes and CGRP fibers were found in WT+SCT mice, and further increase was seen in BDNF over-expression transgene mice. BDNF-overexpression may not only facilitate the recovery of locomotor function via AKT pathway, but also contributed simultaneously to thermal hyperalgesia after SCT.     

Intestinal stem cells and stem cell-based therapy for intestinal diseases

Currently, many gastrointestinal diseases are a major reason for the increased mortality rate of children and adults every year. Additionally, these patients may cope with the high cost of the parenteral nutrition (PN), which aids in the long-term survival of the patients. Other treatment options include surgical lengthening, which is not sufficient in many cases, and intestinal transplantation. However, intestinal transplantation is still accompanied by many challenges, including immune rejection and donor availability, which may limit the transplant’s success. The development of more safe and promising alternative treatments for intestinal diseases is still ongoing. Stem cell-based therapy (SCT) and tissue engineering (TE) appear to be the next promising choices for the regeneration of the damaged intestine. However, suitable stem cell source is required for the SCT and TE process. Thus, in this review we discuss how intestinal stem cells (ISCs) are a promising cell source for small intestine diseases. We will also discuss the different markers were used to identify ISCs. Moreover, we discuss the dominant Wnt signaling pathway in the ISC niche and its involvement in some intestinal diseases. Additionally, we discuss ISC culture and expansion, which are critical to providing enough cells for SCT and TE. Finally, we conclude and recommend that ISC isolation, culture and expansion should be considered when SCT is a treatment option for intestinal disorders. Therefore, we believe that ISCs should be considered a cell source for SCT for many gastrointestinal diseases and should be highlighted in future clinical applications.     

Salmon calcitonin induces pituitary tumor in rats.

Calcitonin is widely used in the treatment of post-menopausal osteoporosis. The present study was designed to investigate the effects of salmon calcitonin (SCT) on the incidence of the pituitary tumors in Sprague-Dawley (SD) rats. Subcutaneous injections of SCT at a dose of 160 IU/kg/day for 6 months reduced body weight and induced one pituitary hyperplasia and three pituitary adenomas in 4 of 5 animals, while 5 controls did not show any changes. Prolactin-positive cells were located at the periphery of the affected pituitaries adjacent to the prolactin-negative adenomas. In addition, serum concentrations of prolactin and TSH were lower than in the controls, although serum calcium or LH levels were not significantly different from the controls. Among 7 animals treated with SCT for 6 months followed by no medication for another 6 months, 5 adenomas were detected, one of which had invasive growth toward the adjacent tissue, whereas only one adenoma was found in 9 controls. These results suggest that SCT administration at a high dose may induce the formation of pituitary adenoma, or may accelerate the development of spontaneous pituitary adenomas, some of which show frequent mitotic figures and invasive growth into the surrounding tissue, possibly resulting in malignant transformation. This indicates the need for caution in considering whether calcitonin injections into patients with osteoporosis as well as Paget's disease may induce such pituitary tumors.     

Capacity for differentiation and normalization of tumor cell populations transplanted into the anterior chamber. IV. Ehrlich ascites carcinoma

The activity of LDH M- and H-forms, nuclear DNA contents and of genome mutation rates in the Ehrlich ascitic carcinoma cells were studied after transplantation to the intraperitoneal cavity, subcutaneous connective tissue (SCT) and the eye anterior chamber (EAC). SCT and EAC cultivations demonstrate the increase of M- to H-forms activity ratio due to a lesser H-form activity; so, LDH profiles appear to be associated with such a spontaneously highly differentiated adenocarcinoma of murine breast cancer. SCT and EAC cultivation leads also to changes in the karyotypic structure of cell population--there are no polyploid cells (DNA content is more than 4c). It may result from a sharp fall in genome mutation rates in the Ehrlich ascitic carcinoma clones following EAC proliferation which appears 47 times lower than those during lung proliferation. The data obtained favor a hypothesis that the increase in differentiation level and decrease in tumorigenety of cancer cells during EAC proliferation may be due to selection of the near-diploid cells and to the reduction in genome mutation rates, which in the whole results in decreasing genotypic and epigenotypic variability in tumor cell populations.     

Pre-service teachers’ perceptions of sluggish cognitive tempo

Sluggish cognitive tempo (SCT) is characterized by a passive form of inattention that may not overtly disrupt classroom goals. Due to the nature of these symptoms, children with SCT may be “falling through the cracks” in schools. The current study examined pre-service teachers’ perceptions of SCT in the classroom. Undergraduate education majors (n = 161) read vignettes describing fictitious fourth-grade boys presenting with symptoms of SCT, attention-deficit/hyperactivity disorder (ADHD), or a non-ADHD-related control: social anxiety disorder (SA), and rated each of the vignettes in terms of their perceptions of the boy described. Results were analyzed using repeated measures ANOVAs and paired-sample t tests. Pre-service teachers viewed all three sets of symptoms as concerning, but viewed ADHD behaviors as the most problematic. These results are promising, as they suggest that pre-service teachers are concerned about both hyperactive (i.e., ADHD) and non-hyperactive behavioral problems (i.e., SCT and SA). Implications and future directions are discussed.     

Stem-cell transplantation for autoimmune diseases

The use of intensive immunosuppressive treatment coupled with BM stem-cell transplantation (SCT) to treat human autoimmune diseases (AID) follows anecdotal observations of responses of AID to allogeneic SCT and an extensive background of experience with SCT in animals with AID. In the last decade, numerous clinical trials have been initiated to explore a potential benefit of (mainly autologous) SCT in advanced and debilitating cases of rheumatoid arthritis, scleroderma, systemic lupus erythematosis and multiple sclerosis. In this review the etiology of AID and the experimental basis of SCT is presented, together with recent clinical results of SCT for AID. While much has been learned about the risks and benefits of SCT in AID, the underlying mechanisms regulating remission and relapse of AID after treatment remain largely unknown.     

Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells

Autoimmune diseases that are resistant to conventional treatment cause severe morbidity and even mortality. In the present study we demonstrate that complete remissions can be achieved in refractory polychondritis and systemic lupus erythematosus (SLE), even at advanced stage, with the use of autologous stem-cell transplantation (SCT). Remissions persisted after reconstitution of the immune system. In the treatment of advanced systemic sclerosis (SSc), stable disease may be achieved with autologous SCT.