Effect of a heat and moisture exchanger on temperature and humidity of inhaled gas in isoflurane-anesthetized dogs.

OBJECTIVE: To investigate the effects of a heat and moisture exchanger (HME) on the temperature and humidity of inhaled gas in isoflurane-anesthetized dogs. STUDY DESIGN: Prospective, interventional study. ANIMALS: A total of four experimental dogs and four client-owned dogs weighing 13.9 ± 7.4 kg (mean ± standard deviation). METHODS: The four experimental dogs were anesthetized on two occasions with and without an intact HME at least 1 week apart. The four client-owned dogs were anesthetized once only for a surgical procedure and assigned to the HME group or no-HME group in alternate order, resulting in six dogs for each group. All dogs were premedicated, anesthetized with propofol and intubated. The HME was connected to the endotracheal tube. Anesthesia was maintained with isoflurane. A digital thermo-hygrometer was placed between the endotracheal tube and HME. The temperature and relative humidity of the inhaled gas were measured every 5 minutes for 60 minutes and the absolute humidity was calculated at each time point. RESULTS: The temperature and absolute humidity of the inhaled gas was significantly higher at 5-60 minutes after intubation in the HME group than in the no-HME group. Absolute humidity was maintained above 29 mg H2O L-1 in the HME group. No significant time-dependent effects on temperature, relative humidity or absolute humidity of the inhaled gas were observed. CONCLUSIONS AND CLINICAL RELEVANCE: The temperature and absolute humidity of the inhaled gas were higher when an HME was used during isoflurane anesthesia in dogs. The use of an HME may reduce the risk of dehydration and dysfunction of the airway mucosal epithelium.

Sedative and physiological effects of brimonidine tartrate ophthalmic solution in healthy cats.

OBJECTIVE: To determine the effects of brimonidine tartrate ophthalmic solution on sedation, heart rate (HR), respiratory frequency (fR), rectal temperature (RT) and noninvasive mean arterial pressure (MAP) in healthy cats. STUDY DESIGN: Randomized, blinded crossover study, with 1 week washout between treatments. ANIMALS: Six healthy purpose-bred cats. METHODS: Brimonidine tartrate ophthalmic solution 0.1% (one or two drops; 58.6 ± 3.3 µg per drop) or a control solution (artificial tear solution) was administered to six healthy cats. Behavioural observations and measurements of HR, fR, RT and MAP were recorded before and at 30, 60, 90, 120, 180, 240, 300 and 360 minutes after topical administration. Behavioural scores were analysed using Friedman's test for repeated measures to evaluate the time effect in each treatment and treatment effect at each time point. Physiological variables (HR, fR, RT and MAP) were analysed using two-way analysis of variance for repeated measures to evaluate the time and treatment effects. The level of significance was set at p < 0.05. RESULTS: Dose-dependent behavioural and physiological responses were noted. A dose of two drops of brimonidine resulted in sedation in the cats and decreased HR and MAP. Significant sedative effects occurred between 30 and 120 minutes and for physiological responses up to 360 minutes. The most frequent adverse reaction was vomiting, occurring within 40 minutes in all six cats administered two drops and five of the six cats administered one drop of brimonidine. CONCLUSIONS AND CLINICAL RELEVANCE: The results demonstrated that ocular administration of brimonidine 0.1% ophthalmic solution induced sedation in cats and some cardiovascular effects usually associated with α2-adrenoceptor agonists. Further studies should be performed to determine clinical applications for this agent in cats.

Effects of medetomidine and xylazine on intraocular pressure and pupil size in healthy Beagle dogs.

OBJECTIVE: To determine the effects of intramuscular (IM) administration of medetomidine and xylazine on intraocular pressure (IOP) and pupil size in normal dogs. STUDY DESIGN: Prospective, randomized, experimental, crossover trial. ANIMALS: Five healthy, purpose-bred Beagle dogs. METHODS: Each dog was administered 11 IM injections of, respectively: physiological saline; medetomidine at doses of 5, 10, 20, 40 and 80 µg kg(-1), and xylazine at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg kg(-1). Injections were administered at least 1 week apart. IOP and pupil size were measured at baseline (before treatment) and at 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours post-injection. RESULTS: A significant decrease in IOP was observed at 6 hours after 80 µg kg(-1) medetomidine compared with values at 0.25 and 0.50 hours, although there were no significant changes in IOP from baseline. In dogs treated with 8.0 mg kg(-1) xylazine, significant reductions in IOP were observed at 4 and 5 hours compared with that at 0.25 hours after administration. In dogs treated with 5, 10, 20 and 40 µg kg(-1) medetomidine and 0.5, 1.0 and 2.0 mg kg(-1) xylazine, there were no significant changes in IOP. Pupil size did not change significantly after any of the medetomidine or xylazine treatments compared with the baseline value. CONCLUSIONS AND CLINICAL RELEVANCE: Low or moderate doses of medetomidine or xylazine did not induce significant changes in IOP or pupil size. In contrast, high doses of medetomidine or xylazine induced significant changes up to 8 hours after treatment, but values remained within the normal canine physiological range. The results of this study suggest a lack of significant change in IOP and pupil size in healthy dogs administered low or moderate doses of xylazine or medetomidine.

Effect of fentanyl constant-rate infusions with or without medetomidine on the minimum infusion rate of propofol required to prevent motor movement in dogs.

Propofol is a potential injectable anesthetic agent used in total intravenous anesthesia. However, the sparing effect of fentanyl and medetomidine on the required propofol dose in dogs remains unclear. We aimed to investigate the effect of fentanyl constant-rate infusion (CRI) with or without medetomidine on the minimum infusion rate of propofol required to prevent motor movement (MIRNM) in dogs. Six healthy purpose-bred dogs were anesthetized on three occasions with propofol alone (loading dose [LD], 8 mg/kg to effect; initial infusion rate [IR], 0.70 mg/kg/min); propofol (LD, 6 mg/kg to effect; IR, 0.35 mg/kg/min) and fentanyl (LD, 2 µg/kg; IR, 0.10 µg/kg/min); or propofol (LD, 4 mg/kg to effect; IR, 0.25 mg/kg/min), fentanyl (LD, 2 µg/kg; IR, 0.10 µg/kg/min), and medetomidine (LD, 2 µg/kg; IR, 0.5 µg/kg/hr) under controlled ventilation. The MIRNM was determined by observing the response to a noxious electrical stimulus. Heart rate, blood pressure, and blood gas analyses were performed at 1, 2, 3, and 4 hr after initiating CRI. The MIRNM (mean [range]) was significantly lower in the propofol-fentanyl-medetomidine group (0.16 [0.10-0.27] mg/kg/min) than that in the propofol-alone group (0.63 [0.47-0.82] mg/kg/min) (P=0.0004). Fentanyl combined with medetomidine did not significantly decrease the mean arterial pressure in dogs receiving propofol CRI 1-3 hr after initiating CRI compared with propofol CRI alone (P>0.9999, P=0.1536, and P=0.0596, respectively), despite inducing a significantly lower heart rate.

Effects of Intravenous Pimobendan on Cardiovascular Parameters in Healthy Sedated Cats.

This study aimed to investigate the effects of intravenous pimobendan on cardiovascular function and to determine the appropriate dose for clinical usage in cats. Six purpose-bred cats received one of the following treatments: intravenous pimobendan at a single dose of 0.075 mg/kg (low dose [LD] group), 0.15 mg/kg (middle dose [MD] group), 0.3 mg/kg (high dose [HD] group), or saline at 0.1 mL/kg (placebo group). Echocardiography and blood pressure measurements were performed before and 5, 15, 30, 45, and 60 minute after drug administration for each treatment. In the MD and HD groups, the fractional shortening, peak systolic velocity, cardiac output, and heart rate increased significantly. There were no significant differences in blood pressure among the groups. Intravenous pimobendan at 0.15-0.3 mg/kg increased the fractional shortening, peak systolic velocity, cardiac output in healthy cats.

Magnetic resonance imaging findings of the primitive neuroectodermal tumour in lumbosacral spinal cord in a cat.

A 5-year-old, castrated, male domestic short-haired cat presented with neurological deficits in the pelvic limbs, back pain and dysuria. Magnetic resonance imaging showed a mass lesion caudal to the L4 vertebrae. In addition, suspected haemorrhage was observed at the cranial aspect of the mass. There was no evidence to support the presence of extravertebral intrusion or vertebral body, osteolysis. Dorsal laminectomy and durotomy were performed to debulk the intraspinal mass. Histopathological and immunohistochemical assessment revealed a primitive neuroectodermal tumour (PNET). To our knowledge, this is the first report to describe the clinical and pathological features and imaging diagnosis of intraspinal PNET without extraspinal invasion in a cat.

Variation in Diffusion Tensor Imaging Parameters in the Cervical and Thoracic Spinal Cord (C1-C5 and C6-T2) Segments of Normal Beagle Dogs.

This study aimed to determine the characteristics and reference values of each vertebra in the cervicothoracic region by performing diffusion tensor imaging (DTI) scans and analyzing DTI parameters in normal Beagle dogs. In five adult Beagles under anesthetic maintenance, DTI was performed using a 1.5-T magnetic resonance imaging (MRI) scanner. Axial DTI was performed using three overlapping slabs to cover the cervical and thoracic spinal cords. After post-processing, DTI parameters were calculated along the entire spinal cord. Among DTI parameters, fractional anisotropy, relative anisotropy, and axonal diffusivity significantly decreased in the caudal direction. However, the apparent diffusion coefficient, radial diffusivity, and mean diffusivity values were not significantly correlated with vertebral levels. We provide evidence for the existence of segment-dependent DTI parameters in the canine cervical spinal cord. Therefore, comparisons of DTI parameters between lesions at different vertebral levels should be avoided unless normative data are available. Furthermore, the DTI data obtained in this study may contribute to the development of a clinical reference for spinal cord evaluation in dogs using DTI parameters.

Phenotypic and molecular characterization of novel pulmonary adenocarcinoma cell lines established from a dog.

Canine pulmonary adenocarcinoma (PAC) resembles human lung tumors in never-smokers, but it is rarer than human pulmonary adenocarcinoma. Therefore, research on canine PAC is challenging. In the present study, we successfully established various novel canine PAC cell lines from a single lesion in a dog, including two parent cell lines and fourteen cloned cell lines, and characterized their cellular properties in vitro. Several of these cell lines showed epithelial-mesenchymal transition (EMT)-like and/or cancer stem cell (CSCs)-like phenotypes. We additionally assessed the sensitivity of the cells to vinorelbine in vitro. Three clonal lines, two of which showed EMT- and CSC-like phenotypes, were resistant to vinorelbine. Furthermore, we evaluated the expression and activation status of EGFR, HER2, and Ras signaling factors. The findings indicated that the cell lines we established preserved the expression and activation of these factors to varying extents. These novel canine PAC cell lines can be utilized in future research for understanding the pathogenesis and development of treatments for canine PAC.

Reducing Effects of Whey Protein Hydrolysate on Coloration of Cured Sausages.

Curing produces a characteristic pink color during meat processing through the production of nitrosyl myoglobin (NOMb), which requires nitric oxide (NO). Nitrites and nitrates in coloring agents are crucial NO sources; however, a reducing agent is necessary to facilitate their chemical conversion to NO. This study aimed to investigate the effect of the reducing properties of whey protein hydrolysate (WPH) on the reddening of cured meat products. Cured and cooked sausage models were treated with WPH, which enhanced the reddening of the meat color and increased the a* value in the models compared with that of the controls. Additionally, ethanol-extracted WPH induced Fe3⁺ reduction, lowered oxidation-reduction potential, and decreased nitrite (NO2-) levels. Moreover, ethanol-extracted WPH promoted the formation of NOMb in myoglobin solution. This effect was also observed when ethanol-extracted WPH treated with maleimide was used, implying that certain peptides rather than the thiol group of WPH are involved in promoting NOMb formation. Furthermore, the peptides that decreased NO2- levels were isolated from ethanol-extracted WPH, identified, and synthesized. These synthesized peptides, particularly the FFVAPFPEVFGK peptide, showed NO2--reducing activity. Hence, WPH may promote the coloration of cured meat products through the reducing potential of the peptides contained within.

Effects of a Multimodal Approach Using Buprenorphine with/without Meloxicam on Food Intake, Body Weight, Nest Consolidating Behavior, Burrowing Behavior, and Gastrointestinal Tissues in Postoperative Male Mice.

Distress affects animal welfare and scientific data validity. There is a lack of reports on the effects of multimodal analgesic approaches in mice. In this study, under the hypothesis that a multimodal analgesic protocol using buprenorphine with meloxicam has analgesic effects, we evaluated the effects of a multimodal analgesic protocol using buprenorphine with meloxicam on the well-being of mice during analgesic administration by changing the dosage of meloxicam. A total of 42 Slc:ICR male mice were categorized into nonsurgical and surgical groups (7 mice per group) and treated with an anesthetic (isoflurane) and analgesics (buprenorphine ± meloxicam). Analgesics were administered for 48 h after treatment. Buprenorphine (subcutaneous; 0.1 mg/kg/8 h) and meloxicam (subcutaneous; 0, 2.5, or 5 mg/kg/24 h) were administered twice. Body weight, food intake, nest consolidation score, and latency to burrow were evaluated. A significant decrease in food intake was observed 24 h after treatment, while a significant increase was observed 48 h post-treatment in all groups. Body weight showed a decreasing trend but was not significantly reduced. Furthermore, stomach, duodenum, and jejunum tissues showed no morphological abnormalities. Significant differences in burrow diving scores and the latency to burrow were observed between some groups, but these were not regarded as a consequence of the surgery and/or the meloxicam dose. When buprenorphine and meloxicam were combined, administering up to 5 mg/kg/day of meloxicam for 48 h to male mice after abdominal surgery had no significant negative effects on any tested parameters. In conclusion, a multimodal analgesic protocol of buprenorphine with meloxicam is among the options for increasing well-being in mice following abdominal surgery.

Effect of Hot Water Bottles on Body Temperature during Magnetic Resonance Imaging in Dogs under General Anesthesia: A Retrospective Study.

Prevention of hypothermia induced by anesthesia and enhanced by low environmental temperatures is difficult in magnetic resonance imaging (MRI) examinations in dogs as forced warming devices, including magnetic materials, are not acceptable for use in the MRI room. A hot water bottle (HWB) can be carried into an MRI examination room and can contribute to the prevention or attenuation of hypothermia. Here, we retrospectively investigated the effects of HWB on body temperature during MRI examinations in dogs under general anesthesia (GA). From anesthesia records of the Veterinary Medical Teaching Hospital, Okayama University of Science, validated data of 100 dogs that underwent an MRI examination under GA were obtained and divided into the following two groups: one group received HWB, while the other did not. Decrease in rectal temperature 15 min after intubation was significantly smaller in the group using HWB than in the group without HWB. In conclusion, the use of hot water bottles might be one of the methods to attenuate hypothermia in the early period but should not be expected for complete prevention of hypothermia, and it was not recommendable necessarily for body temperature management during MRI examinations in dogs under general anesthesia.

Distal renal tubular acidosis and lethargy associated with zonisamide treatment in a dog with idiopathic epilepsy.

A 3-year-old neutered male golden retriever administered zonisamide for the treatment of seizures showed lethargy and had normal anion gap metabolic acidosis with hypokalaemia, hyperchloremia, and alkaline urine. The serum zonisamide concentration was close to the upper limit, which raised a suspicion of adverse effects of zonisamide. This is the first report showing that the fractional excretion of bicarbonate after compensation for the plasma bicarbonate concentration by a sodium bicarbonate infusion was approximately 5%, indicating distal renal tubular acidosis (RTA). The serum zonisamide concentration decreased, and adverse effects were abated by reducing the zonisamide dosage. Diagnostic therapy with bicarbonate served as a means of compensating for bicarbonate deficiency and contributed to the clinical diagnosis of the condition in zonisamide-associated RTA in dogs.

Expression profile of immunoregulatory factors in canine tumors.

Cancers utilize a variety of molecules to escape host immune responses. Better understanding the immune environment surrounding cancer may facilitate application of innovative cancer immunotherapies, such as immune checkpoint inhibitors, to dogs as well as humans. In this study, we screened the expression of 20 immune regulatory molecules in diverse canine tumors (n = 59). Quantitative RT-PCR (qPCR) analysis revealed that some immune regulatory molecules, such as LGALS9 (coding Galectin-9) and CD48, were expressed in most canine tumors, but other molecules, such as CD274 (coding PD-L1), IL4I1, PVR, TNFSF18, ICOSLG, and TNFSF4, were rarely expressed. NECTIN2 was highly expressed in epithelial tumors but was low in non-epithelial tumors. In contrast, VSIR and CD200 expressions were low in epithelial tumors but high in non-epithelial tumors. Interestingly, several tumors expressed distinctive immunoregulatory factors. Hepatocellular carcinomas expressed FGL1, mast cell tumors expressed PDCD1LG2 (coding PD-L2), transitional cell carcinomas expressed VTCN1 (coding B7x), and lymphomas and squamous cell carcinomas expressed CD70. Consistent with qPCR results, immunofluorescence staining confirmed that hepatocellular carcinomas expressed FGL-1 protein. Thus, this study reveals the expression profile of immunoregulatory molecules in canine tumors and opens the door to better understanding the relationship between canine tumors and host immunity.

Effects of Pre-Anesthesia Anxiety on Propofol Induction Dose in Cats.

In humans, peri-anesthesia anxiety reportedly increases the anesthetic requirements for anesthesia induction. However, no studies have been conducted on cats regarding the effects of anxiety on anesthesia induction or anesthetic-mediated physiological changes. Therefore, we intended to investigate the effect of pre-anesthesia anxiety in healthy cats on the propofol dose required for anesthesia induction, and its impact on behavioral and physiological evaluations. The cats were placed in either a calm (CAL) or tense (ANX) environment. We performed physiological and behavioral evaluations before and after each environmental acclimatization period. Anesthesia was induced using propofol. We recorded the total dose of propofol administered for each clinical sign observed during anesthesia induction. The post-acclimatization behavioral evaluation score was significantly higher in the ANX group than the pre-acclimatization score. However, there was no significant difference in the propofol dose required for each clinical sign in the ANX or CAL groups. There were also no significant differences in the physiological evaluations between the ANX and CAL groups. Therefore, pre-anesthesia anxiety felt by cats did not affect propofol-mediated anesthesia induction.

Establishment of a canine lens epithelial cell line.

Some immortalized lens epithelial cell lines have been established and are useful for molecular analysis. The establishment of additional cell lines must, however, enable a variety of in-vitro examinations. The objective of this study was to establish a new canine lens epithelial cell line by isolating CLC-1 cells from the lens tissue of a dog with cataracts. In CLC-1 cells, transforming growth factor beta (TGF-ß) treatment significantly decreased gene expression of an epithelial marker and elevated that of mesenchymal markers; these characteristics are similar to those of a human lens epithelial cell line. Interestingly, CLC-1 cells exhibited lower expression of an epithelial marker and higher expression of mesenchymal markers than an anterior lens capsule. These results suggest that CLC-1 cells were derived from a cell population that was committed to epithelial-mesenchymal transition in cataract lens tissue. In conclusion, CLC-1 cells could be useful for analyzing molecular pathogenesis in canine cataracts.

Certaines lignées de cellules épithéliales du cristallin immortalisées ont été établies et sont utiles pour analyse moléculaire. L'établissement de lignées cellulaires supplémentaires doit cependant permettre une variété d'examens in vitro. L'objectif de cette étude était d'établir une nouvelle lignée cellulaire épithéliale du cristallin canin en isolant les cellules CLC-1 du tissu du cristallin d'un chien atteint de cataracte. Dans les cellules CLC-1, le traitement par le facteur de croissance transformant bêta (TGF-ß) a significativement diminué l'expression génique d'un marqueur épithélial et élevé celle des marqueurs mésenchymateux; ces caractéristiques sont similaires à celles d'une lignée cellulaire épithéliale du cristallin humain. Fait intéressant, les cellules CLC-1 présentaient une expression inférieure d'un marqueur épithélial et une expression plus élevée de marqueurs mésenchymateux qu'une capsule antérieure du cristallin. Ces résultats suggèrent que les cellules CLC-1 étaient dérivées d'une population cellulaire qui était impliquée dans la transition épithéliale-mésenchymateuse dans le tissu du cristallin de la cataracte. En conclusion, les cellules CLC-1 pourraient être utiles pour analyser la pathogenèse moléculaire dans les cataractes canines.(Traduit par Docteur Serge Messier).

Effects of Multimodal Analgesic Protocol, with Buprenorphine and Meloxicam, on Mice Well-Being: A Dose Finding Study.

The anesthetic or analgesic agent of choice, route and frequency of anesthetic or analgesic administration, and stressors induce distress during the perioperative period. We evaluated a multimodal analgesic protocol using buprenorphine and meloxicam on the well-being of mice. Twenty-four Slc:ICR male mice were divided into control, anesthesia + analgesia, and surgery + anesthesia + analgesia groups. Tap water (orally: PO) and water for injection (subcutaneous: SC) were administered to the control group. Buprenorphine was administered twice (SC, 0.1 mg/kg/8 h) and meloxicam was administered thrice (PO, 5 mg/kg/24 h) to the anesthesia + analgesia and surgery + anesthesia + analgesia groups. The mice were subjected to laparotomy and assessed for several parameters. Even in absence of surgical pain, the anesthesia + analgesia group presented the same negative effects as the surgery + anesthesia + analgesia group. This multimodal analgesic protocol for mice was expected to have an analgesic effect on pain associated with laparotomy but was not sufficient to prevent food intake and weight decrease. This does not negate the need to administer analgesics, but suggests the need to focus on and care not only about the approach to relieve pain associated with surgery, but also other types of distresses to minimize negative side effects that may interfere with postoperative recovery in mice.

Local Hemodynamic Changes Immediately after Correction of an Aberrant Right Subclavian Artery in a Dog: A Contrast Computed Tomographic Study.

A 1-year-old female Akita dog was referred for intermittent regurgitation. Computed tomographic angiography (CTA) showed an aberrant right subclavian artery (ARSA), resulting in constriction of the esophagus. After surgical ligation of the ARSA, CTA showed that the ARSA was not enhanced by contrast medium, and that sufficient collateral circulation of the right forelimb was supplied through the vertebral artery. Furthermore, the right and left vertebral arteries merged into the basilar artery at the level of the atlas, and no abnormal expansion of the ventral spinal artery was observed. Overall, we demonstrated the importance of post-surgical CTA for identification of surgical complications, including the formation of abnormal vessel alterations.

Dysuria Associated with Non-Neoplastic Bone Hyperplasia of the Os Penis in a Pug Dog.

A three-year-old male Pug presented with a three-year history of urolithiasis and repeated urethral obstruction. Biochemical analysis, ultrasonography, and retrograde urethrocystography revealed probable portosystemic shunt and incomplete urethral obstruction due to uric acid ammonium calculi. Enhanced computed tomography (CT) revealed portosystemic shunt and proliferation of the osseous tissue of the os penis, which was surgically removed. Histopathologically, the excised osseous tissue comprised bland lamellar bone without atypia or inflammation. Hyperplasia of the os penis was diagnosed based on the image findings and histopathology. The dysuria improved postoperatively. This is the first report of dysuria associated with non-neoplastic bone hyperplasia of the os penis in a dog. Careful evaluation of the os penis by CT is needed for accurate diagnosis in case of repeated penile urethral obstruction.

Mydriasis associated with local dysfunction of parasympathetic nerves in two dogs.

In clinical practice, photophobia resulting from persistent mydriasis may be associated with dysfunction of ocular parasympathetic nerves or primary iris lesions. We encountered a 5-year-old Miniature Dachshund and a 7-year-old Shih Tzu with mydriasis, abnormal pupillary light reflexes, and photophobia. Except for sustained mydriasis and photophobia, no abnormalities were detected on general physical examination or ocular examination of either dog. We performed pharmacological examinations using 0.1% and 2% pilocarpine to evaluate and diagnose parasympathetic denervation of the affected pupillary sphincter muscles. On the basis of the results, we diagnosed a pupillary abnormality due to parasympathetic dysfunction and not to overt primary iris lesions. The test revealed that neuroanatomic localization of the lesion was postciliary ganglionic in the first dog.

A laryngeal inflammatory polyp in a miniature dachshund.

A 15-year old, female miniature dachshund was presented for a 5-year history of progressive dyspnoea. A laryngeal mass was detected on cervical radiographs. Surgery was performed 5 days later to reduce the volume of the mass and to obtain biopsy samples; the dyspnoea improved. Based on the histopathological findings, the mass was diagnosed as inflammatory polyp. This case of inflammatory polyp in the larynx suggests that it should be listed in the differential diagnoses for laryngeal masses in dogs and that surgical treatment may be curative.