A noncyclical analog of salmon calcitonin (N alpha-propionyl Di-Ala1,7,des-Leu19 sCT) retains full potency without inducing anorexia in rats

A new analog of salmon calcitonin (N alpha-propionyl Di-Ala1,7,des-Leu19 sCT; RG-12851; here termed CTR), which lacks the ring structure of native calcitonin, was tested for biological activity in several in vitro and in vivo assay systems. The analog (CTR) and salmon calcitonin (sCT) stimulated kidney cell adenylate cyclase activity and inhibited bone resorption in organ cultures of fetal rat long bones with similar potencies and efficacies. Furthermore, CTR and sCT, at similar doses, induced comparable hypocalcemic responses in mice following sc injection or infusions. However, unlike sCT, CTR did not induce anorexia and weight loss in rats following sc injection. These data suggest that the ring structure of sCT may be important for the anorexigenic effect but is not required for effect on bone resorption or calcium homeostasis. Clinical studies appear warranted as, potentially, CTR might induce fewer side effects than does sCT.     

Dynamic Postural-Stability Deficits After Cryotherapy to the Ankle Joint

Context

 Decreased postural stability is a primary risk factor for lower limb musculoskeletal injuries. During athletic competitions, cryotherapy may be applied during short breaks in play or during half-time; however, its effects on postural stability remain unclear.

Objective

 To investigate the acute effects of a 15-minute ankle-joint cryotherapy application on dynamic postural stability.

Design

 Controlled laboratory study.

Setting

 University biomechanics laboratory.

Patients or Other Participants

 A total of 29 elite-level collegiate male field-sport athletes (age = 20.8 ± 1.12 years, height = 1.80 ± 0.06 m, mass = 81.89 ± 8.59 kg) participated.

Intervention(s)

 Participants were tested on the anterior (ANT), posterolateral (PL), and posteromedial (PM) reach directions of the Star Excursion Balance Test before and after a 15-minute ankle-joint cryotherapy application.

Main Outcome Measure(s)

 Normalized reach distances; sagittal-plane kinematics of the hip, knee, and ankle joints; and associated mean velocity of the center-of-pressure path during performance of the ANT, PL, and PM reach directions of the Star Excursion Balance Test.

Results

 We observed a decrease in reach-distance scores for the ANT, PL, and PM reach directions from precryotherapy to postcryotherapy (P < .05). No differences were observed in hip-, knee-, or ankle-joint sagittal-plane kinematics (P > .05). We noted a decrease in mean velocity of the center-of-pressure path from precryotherapy to postcryotherapy (P < .05) in all reach directions.

Conclusions

 Dynamic postural stability was adversely affected immediately after cryotherapy to the ankle joint.Key Words: postural balance, lower limb, kinetics

Key Points

• A 15-minute cryotherapy application to the ankle joint decreased cutaneous temperature recorded over the anterior talofibular ligament and deltoid ligament.
• Reach distances in the anterior, posterolateral, and posteromedial directions of the Star Excursion Balance Test and center-of-pressure mean velocity decreased after cryotherapy.
• A 15-minute cryotherapy application negatively influenced dynamic postural-stability performance.
• Elite-level field-based athletes should undergo a rewarming period before returning to participation after cryotherapy to the ankle joint to ensure they are not predisposed to injury due to decreased dynamic postural stability.

Cryotherapy is a treatment modality that clinicians commonly use to promote quicker recovery from soft tissue injury in athletes to expedite return to participation. It has been described as the application of cold therapy to living tissues that results in a lower tissue temperature^1,2 and often is used as an immediate treatment method to relieve the acute pain of soft tissue injuries.¹The proposed physiologic benefits of cryotherapy for injury have been widely reported. Cryotherapy facilitates edema reduction, produces analgesia,^2,3–6 reduces muscle temperature,⁷ and reduces injury-induced inflammation.^8,9 If an athlete incurs a mild sprain or contusion to the ankle joint in a game, the accepted practice during a break in participation (eg, during a half-time period) is to apply cryotherapy to the affected area.In contrast to the aforementioned positive physiologic effects, Bleakley et al¹⁰ reported in a recent literature review that cryotherapy application negatively affected at least 1 of the following outcomes: vertical-jump height, sprint time, or agility performance. These tasks are integral components of field-based sports, and any decrement in performance could predispose individuals to injury during participation. Pritchard and Saliba¹¹ suggested that athletic performance may be adversely affected when athletes return to participation immediately after cryotherapy. Furthermore, Costello and Donnelly¹² reported that cryotherapy negatively affects knee-joint positional sense. Uchio et al¹³ observed that a 15-minute cryotherapy application increased knee-joint stiffness and decreased knee-joint position sense acuity. Stal et al¹⁴ reported that ankle-joint sensorimotor control as quantified by static postural stability was negatively affected by a 20-minute cooling procedure known as hypothermic anesthesia, which is similar to a cryotherapy application.Postural stability refers to the ability to control the center of mass in relation to the base of support to prevent falls¹⁵ and is considered a fundamental component required for performing movement skills.¹⁶ Dynamic postural stability can be defined and measured as an assessment of an individual''s ability to maintain balance while transitioning from a dynamic to a static state.¹⁷ It is an essential part of an athlete''s physical attributes, especially for field sports, given their dynamic nature.¹⁸ Both static and dynamic postural stability result from the complex coordination of central processing from visual, vestibular, and somatosensory pathways, as well as the resultant efferent response.¹⁹Static-standing balance ability decreases after cryotherapy application. Cross et al²⁰ reported that after cryotherapy to the lower extremity, study participants had difficulty maintaining their balance on the treated extremity. More recently, Kernozek et al²¹ reported a deficit in mediolateral (ML) ground reaction force variability on the test leg immediately after a 20-minute cryotherapy application to the ankle joint, with a mean difference of 0.48 N relative to precryotherapy measures (P < .001; d = 1.20). At the 10-minute and 20-minute measurements postcryotherapy, participants continued to exhibit deficits in static-standing balance. However, traditional laboratory measures of postural stability, including static single-legged stance on instrumented force plates, may not be sensitive enough to detect postural-stability deficits associated with lower limb injury.²² Furthermore, Hrysomallis et al²³ indicated that postural-stability performance in static positions cannot be extrapolated to dynamic postural-stability performance, concluding that it is not advisable to infer the latter based on the former. Douglas et al²⁴ reaffirmed this conclusion, postulating that measures of dynamic standing balance may better represent the demands of the lower extremity during functional tasks and, therefore, may be a more appropriate assessment than static standing balance. In addition, Hrysomallis²⁵ showed that Australian Rules football players with an increased ML center-of-pressure (COP) excursion incurred at least twice as many ankle-ligament injuries as players with average or good postural stability. Kernozek et al²¹ and Douglas et al²⁴ observed that cryotherapy debilitated dynamic postural stability, potentially increasing the risk of lower limb injury.Considering the potential shortcomings of static postural-stability testing, our contention was that further investigations of the effects of cryotherapy application to the ankle joint on dynamic postural-stability performance are warranted. One potential method to investigate the influence of ankle-joint cryotherapy application on dynamic postural-stability performance is to use the Star Excursion Balance Test (SEBT) as a primary assessment, supplemented by lower limb sagittal-plane motion analysis and force-plate–derived kinetic assessment. Therefore, the purpose of our study was to evaluate the acute influence of a 15-minute cryotherapy application to the ankle joint on dynamic postural stability as quantified by performance on selected reach directions of the SEBT, associated lower limb sagittal-plane kinematic profiles, and kinetic measures of postural stability. We hypothesized that a 15-minute cryotherapy application to the ankle joint would result in decreased reach distances on the selected directions of the SEBT and altered sagittal-plane ankle-joint kinematics and kinetic measures of postural stability.     

Blockade of autocrine stimulation in simian sarcoma virus-transformed cells reverses down-regulation of platelet-derived growth factor receptors.

The viral (v)-sis oncogene encodes a protein (p28sis) that is structurally homologous to platelet-derived growth factor (PDGF). We have shown that simian sarcoma virus (SSV)-transformed cells containing the v-sis oncogene release a Mr 20,000 substance that is recognized by antisera to synthetic peptide sequences contained in p28sis. Medium conditioned by SSV-transformed cells competes with 125I-labeled PDGF for specific PDGF receptor sites, initiates DNA synthesis, and stimulates tyrosine phosphorylation of the PDGF receptor when added to normal cells. When normal cells are co-cultured with SSV-transformed cells, the PDGF receptors of the normal cells are down-regulated by factors released from the transformed cells. Thus, SSV-transformed cells release material that is functionally similar to PDGF. We have used anti-phosphotyrosine antibodies to purify PDGF receptors and to detect PDGF-stimulated receptors in normal cells. SSV-transformed cells have no PDGF receptors detectable by these antibodies or by 125I-labeled PDGF binding studies. However, when SSV-transformed cells are exposed to suramin, a compound that blocks binding of PDGF to its receptors, the receptors reappear on the cell surface and within 8 hr are present at the same levels as in control cells. These "new" receptor sites can be phosphorylated in response to PDGF. Thus, the absence of PDGF receptors in SSV-transformed cells is due to down-regulation of the receptors by an autocrine mechanism that can be blocked by suramin.     

Immune parameter analysis of children with sickle cell disease on hydroxycarbamide or chronic transfusion therapy

Sickle cell disease (SCD) is increasingly appreciated as an inflammatory condition associated with alterations in immune phenotype and function. In this cross‐sectional study we performed a multiparameter analysis of 18 immune markers in 114 paediatric SCD patients divided by treatment group [those receiving hydroxycrabamide (HC, previously termed hydroxyurea), chronic transfusion (CT), or no disease‐modifying therapy] and 29 age‐matched African American healthy controls. We found global elevation of most immune cell counts in SCD patients receiving no disease‐modifying therapy at steady state. Despite the decrease in percentage of haemoglobin S associated with CT therapy, the abnormal cellular immune phenotype persisted in patients on CT. In contrast, in both univariate and multivariate analysis, treatment with HC was associated with normalization of the vast majority of leucocyte populations. This study provides additional support for HC treatment in SCD, as it appears that HC decreases the abnormally elevated immune cell counts in patients with SCD.     

Pulmonary adenocarcinoma T1N0M0 and its classification

Over the last decade, use of the term bronchioloalveolar carcinoma (BAC) has come under constant scrutiny as some consider it an anachronism or a term that provides incorrect information about this neoplasm. To that extent, it has recently been suggested to replace the term BAC with that of in situ adenocarcinoma (AIS) or minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure bronchioloalveolar growth (AIS) or predominant bronchioloalveolar growth and ≤5-mm invasion (MIA). However, as of today, there is no comprehensive study of these tumors, and most of what has been published in this context is based on a review of the literature that focused on scattered short series of cases describing either small adenocarcinomas or BAC. More recently, a large series of cases of a more comprehensive nature that included all early-stage adenocarcinomas (T1N0M0) has cast some doubt regarding the need for the proposed change in nomenclature. At the same time, it was suggested that if indeed that notion is maintained, a more serious and comprehensive study of actual cases must be undertaken. The details of the issues surrounding this subject are presented in this review.