Months In Dogs Research Articles

Spontaneous Course of Biliary Sludge Over 12 Months in Dogs with Ultrasonographically Identified Biliary Sludge.

BackgroundBiliary sludge is associated with gallbladder (GB) dysmotility and mucus hypersecretion suggesting a link between biliary sludge and the formation of GB mucoceles (GBM). If biliary sludge progresses to GBM, treatment to reduce the production and progression of sludge is warranted.Hypothesis/ObjectivesThe objective of this study was to determine the course of biliary sludge in dogs.AnimalsSeventy‐seven healthy, client‐owned dogs ≥4 years of age screened for biliary sludge; 45 affected dogs identified.MethodsProspective, observational design. Serial ultrasound examinations were evaluated at 3, 6, 9, and 12 months to monitor degree of sludge based on proportion of GB filled with sludge (mild [0.01–24.4%], moderate [24.5–49.4%], moderate to severe [49.5–74.4%], severe [74.5–100%]), gravity dependency of sludge, and GB dimensions.ResultsAfter 1 year of follow‐up, the degree of sludge was mild (34%), moderate (47%), moderate to severe (13%), severe (3%), or absent (3%). There was no significant difference in median degree of sludge over 1 year (P = .36). There were no significant changes in the gravity dependency of sludge over 1 year. A subset of dogs, 24%, with initial gravity‐dependent sludge developed a combination of nondependent and dependent sludge. Dogs had resolved (2%), decreased (19%), static (40%), increased (29%), or recurrent (10%) sludge at the conclusion of the study.Conclusions and Clinical ImportanceBiliary sludge was prevalent, affected dogs remained asymptomatic, and it rarely resolves in healthy dogs over a period of 1 year. Some dogs developed nongravity‐dependent sludge within 1 year, which might indicate changes in consistency of sludge.

ASSOCIATION BETWEEN COMPUTED TOMOGRAPHIC CHARACTERISTICS AND FRACTURES FOLLOWING STEREOTACTIC RADIOSURGERY IN DOGS WITH APPENDICULAR OSTEOSARCOMA.

The objective of this observational, descriptive, retrospective study was to report CT characteristics associated with fractures following stereotactic radiosurgery in canine patients with appendicular osteosarcoma. Medical records (1999 and 2012) of dogs that had a diagnosis of appendicular osteosarcoma and undergone stereotactic radiosurgery were reviewed. Dogs were included in the study if they had undergone stereotactic radiosurgery for an aggressive bone lesion with follow-up information regarding fracture status, toxicity, and date and cause of death. Computed tomography details, staging, chemotherapy, toxicity, fracture status and survival data were recorded. Overall median survival time (MST) and fracture rates of treated dogs were calculated. CT characteristics were evaluated for association with time to fracture. Forty-six dogs met inclusion criteria. The median overall survival time was 9.7 months (95% CI: 6.9-14.3 months). The fracture-free rates at 3, 6, and 9 months were 73%, 44%, and 38% (95% CI: 60-86%, 29-60%, and 22-54%), respectively. The region of bone affected was significantly associated with time to fracture. The median time to fracture was 4.2 months in dogs with subchondral bone involvement and 16.3 months in dogs without subchondral bone involvement (P-value = 0.027, log-rank test). Acute and late skin effects were present in 58% and 16% of patients, respectively. Findings demonstrated a need for improved patient selection for this procedure, which can be aided by CT-based prognostic factors to predict the likelihood of fracture.

Serologic Survey of Plague in Animals, Western Iran

Serologic Survey of Plague in Animals, Western Iran

Survival study of 86 bitches with mammary tumors treated at the Veterinary Hospital of the University Anhembi Morumbi, São Paulo, Brazil

Results Among the 154 tumors analyzed, 149 (96.7%) were neoplasms (benign and malignant) and 5 (3.3%) were nonneoplastic lesions. For statistical analysis, mongrel (30.2%) and Poodles (26.7%) were a lot more affected breeds, age between 9 and 12 years (62.8%) was the most frequent of all, 60,4% (90/149) of neoplastic formations were benign and 39,6% (59/149) were malignant. 24,4% (12/49) of all malignant tumors patients had metastasis. Dogs whose tumors were less than 4 cm had no significantly increased duration of survival with a median of 15,3 month versus 17,4 months for dogs with tumors greater than 4 centimeters (p=0,327). Dogs with metastasis lived a median of 10,7 months versus 18,3 months for dogs without them (p<0,01). Patients treated with surgery had 17,3 months of median survival rate versus surgery plus chemotherapy submitted dogs had 13,8 months (p=0,319). Dogs with malignant tumors in stage I, II, III, IV and V had, respectively, 21, 18,4 , 14,9 , 17,2 and 8,8 months of survival (p<0,01).

Target animal safety study of meloxicam administered via transmucosal oral spray (Promist® technology) for 6 months in dogs

This study evaluated the safety of meloxicam administered via transmucosal oral spray (TMOS) at 1, 2, 3 and 5 times the maximum proposed dose for 6months in dogs. After baseline assessments, 40 Beagles (20M, 20F) were randomized to gender-balanced groups administered either water or meloxicam TMOS at 1, 2, 3 and 5 times the maximum proposed dose once daily for 26weeks. Dogs were subjected to daily food consumption measurements and clinical and dose site observations. Periodic evaluations were made of body weight, physical examination, clinical pathology, urinalysis, buccal mucosal bleeding time (BMBT) and gastroduodenal endoscopy. At study completion, all dogs were subjected to gross necropsy. Histopathology was performed on tissues from dogs in groups 0X and 5X and from selected tissues in other dose groups. Clinical signs of previously reported NSAID-associated gastrointestinal upset were noted with higher frequency in meloxicam-dosed animals than in controls. Despite the presence of statistically significant effects on some clinicopathological variables, no toxicologically relevant dose-associated effects were determined on these or on food consumption, dose site observations, body weight, physical examination, urinalysis, BMBT, endoscopic examination or gross and histopathological examination of necropsy tissues.

Long-Term Efficacy Following Readministration of an Adeno-Associated Virus Vector in Dogs with Glycogen Storage Disease Type Ia

Glycogen storage disease type Ia (GSD-Ia) is the inherited deficiency of glucose-6-phosphatase (G6Pase), primarily found in liver and kidney, which causes life-threatening hypoglycemia. Dogs with GSD-Ia were treated with double-stranded adeno-associated virus (AAV) vectors encoding human G6Pase. Administration of an AAV9 pseudotyped (AAV2/9) vector to seven consecutive GSD-Ia neonates prevented hypoglycemia during fasting for up to 8 hr; however, efficacy eventually waned between 2 and 30 months of age, and readministration of a new pseudotype was eventually required to maintain control of hypoglycemia. Three of these dogs succumbed to acute hypoglycemia between 7 and 9 weeks of age; however, this demise could have been prevented by earlier readministration an AAV vector, as demonstrated by successful prevention of mortality of three dogs treated earlier in life. Over the course of this study, six out of nine dogs survived after readministration of an AAV vector. Of these, each dog required readministration on average every 9 months. However, two were not retreated until >34 months of age, while one with preexisting antibodies was re-treated three times in 10 months. Glycogen content was normalized in the liver following vector administration, and G6Pase activity was increased in the liver of vector-treated dogs in comparison with GSD-Ia dogs that received only with dietary treatment. G6Pase activity reached approximately 40% of normal in two female dogs following AAV2/9 vector administration. Elevated aspartate transaminase in absence of inflammation indicated that hepatocellular turnover in the liver might drive the loss of vector genomes. Survival was prolonged for up to 60 months in dogs treated by readministration, and all dogs treated by readministration continue to thrive despite the demonstrated risk for recurrent hypoglycemia and mortality from waning efficacy of the AAV2/9 vector. These preclinical data support the further translation of AAV vector-mediated gene therapy in GSD-Ia.

Retrospective Evaluation of Urethral Bovine Cross‐Linked Collagen Implantation for Treatment of Urinary Incontinence in Female Dogs

Transurethral collagen injections are an alternative treatment for canine urinary incontinence. There is controversy regarding the long-term effectiveness of collagen and the impact urethral coaptation and injection site have on outcome. To evaluate outcome and client satisfaction after urethral collagen injections, and correlation between degree of urethral coaptation and collagen placement with outcome. Thirty-six procedures on 31 dogs, 10 with ureteral ectopia. Retrospective review of records and video evaluation of injection procedures. Follow-up communication with owners was performed between 1 and 56 months after bovine cross-linked collagen implantation to evaluate duration of continence, need for additional medical therapy, and owner satisfaction. Continence score was evaluated before and after the procedure, and after additional medical therapy, if needed. Injection location and degree of urethral coaptation was assessed with respect to duration of continence. Dogs had a significant increase in continence score after the procedure. Mean (SD) duration of continence in dogs without addition of medication was 16.4 (15.2) months, and 5.2 (4.3) months in dogs needing additional medical therapy. No significant difference was found with respect to degree of coaptation. Median client satisfaction with the procedure was 100%. Transurethral collagen implantation may be a viable option for treatment of female dogs with urethral sphincter mechanism incompetence, particularly after medical failure. Duration and degree of improvement are variable. Client satisfaction was excellent despite lack of complete continence in some dogs, and highlights the importance of discussing outcome expectations with owners.

Evaluation of 12- and 24-month survival rates after treatment with masitinib in dogs with nonresectable mast cell tumors

To evaluate the effectiveness of masitinib for the treatment of nonresectable mast cell tumors (MCTs) in dogs at 12 and 24 months after onset of treatment. 132 dogs with nonresectable grade 2 or 3 MCTs. Dogs received masitinib (12.5 mg/kg/d, PO; n = 106) or a placebo (26). After 6 months, treatment was extended with tumor assessments at 3-month intervals until detection of disease progression. Endpoints were tumor response and overall survival rate and time. In dogs with nonresectable MCTs, masitinib significantly improved survival rate, compared with results for the placebo, with 59 of 95 (62.1%) and 9 of 25 (36.0%) dogs alive at 12 months and 33 of 83 (39.8%) and 3 of 20 (15.0%) dogs alive at 24 months, respectively. Median overall survival time was 617 and 322 days, respectively. Tumor control at 6 months had a high predictive value for 24-month survival, with high specificity (88%) and sensitivity (76%), whereas short-term tumor response (within 6 weeks) had a poor predictive value. Complete responses at 24 months were observed in 6 of 67 (9.0%) dogs with nonresectable MCTs treated with masitinib. Masitinib significantly increased survival rates at 12 and 24 months in dogs with nonresectable MCTs. Control of disease at 6 months, but not best response at 6 weeks, was predictive of long-term survival in dogs treated with masitinib, which suggested that short-term response may be irrelevant for assessing clinical efficacy of tyrosine kinase inhibitors for treatment of MCTs.

Causas de óbito e razões para eutanásia em uma população hospitalar de cães e gatos

Com o objetivo de determinar as principais causas de morte em cães e gatos, foram analisadas informações correspondentes às fichas clínicas de cães e gatos provenientes de um hospital veterinário universitário entre julho de 2005 e julho de 2009. Durante o período estudado foram atendidos 2243 casos novos, sendo 2075 cães e 168 gatos. Em cães, o percentual de óbito foi de 10,6% (220/2075) e em gatos, 8,92% (15/168). A idade média quando do óbito em cães e gatos foi de 59,97 e 82,79 meses, respectivamente. Em cães, as principais causas de morte e razões para eutanásia foram distúrbios infecciosos ou parasitários, distúrbios causados por agentes físicos e neoplasias. Exceto pela idade, as demais características de resenha não influenciaram a expectativa de vida ou a causa de morte em cães. Em gatos, distúrbios provocados por agentes físicos e distúrbios urinários foram os principais motivos que resultaram na morte do animal. Os resultados observados identificam a necessidade de medidas profiláticas que possibilitarão maior expectativa de vida e, consequentemente, alteração na frequência das principais causas de morte e razões para eutanásia em cães e gatos.

Pharmacokinetics and Disposition of Rilpivirine (TMC278) Nanosuspension as a Long-Acting Injectable Antiretroviral Formulation

The next-generation human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) was administered in rats and dogs as single intramuscular (IM) or subcutaneous (SC) injections, formulated as a 200-nm nanosuspension. The plasma pharmacokinetics, injection site concentrations, disposition to lymphoid tissues, and tolerability were evaluated in support of its potential use as a once-monthly antiretroviral agent in humans. Rilpivirine plasma concentration-time profiles showed sustained and dose-proportional release over 2 months in rats and over 6 months in dogs. The absolute bioavailability approached 100%, indicating a complete release from the depot, in spite of rilpivirine concentrations still being high at the injection site(s) 3 months after administration in dogs. For both species, IM administration was associated with higher initial peak plasma concentrations and a more rapid washout than SC administration, which resulted in a stable plasma-concentration profile over at least 6 weeks in dogs. The rilpivirine concentrations in the lymph nodes draining the IM injection site exceeded the plasma concentrations by over 100-fold 1 month after administration, while the concentrations in the lymphoid tissues decreased to 3- to 6-fold the plasma concentrations beyond 3 months. These observations suggest uptake of nanoparticles by macrophages, which generates secondary depots in these lymph nodes. Both SC and IM injections were generally well tolerated and safe, with observations of a transient inflammatory response at the injection site. The findings support clinical investigations of rilpivirine nanosuspension as a long-acting formulation to improve adherence during antiretroviral therapy and for preexposure prophylaxis.

Comparison between three adjuvants for a vaccine against canine leishmaniasis: In vitro evaluation of macrophage killing ability

The aim of this study was to evaluate, in terms of dog macrophage killing ability in vitro, a vaccine based on Leishmania infantum promastigote soluble antigen (LSA) formulated with three different adjuvants (BCG, AdjuPrime, MPL/TDM/CWS). A significant increase of the macrophage killing ability was observed in dogs vaccinated with LSA+MPL/TDM/CWS after 1 month from vaccination. A similar increase of macrophage parasitocidal ability was present only after 5 months in dogs vaccinated with LSA+BCG or LSA+AdjuPrime. In all dogs the augmented killing percentage was still present after 12 months from vaccination. Therefore, in particular LSA+MPL/TDM/CWS vaccine seems promising for further studies in dogs.

Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment

Long-acting parenteral formulations of antiretrovirals could facilitate maintenance and prophylactic treatment in HIV. Using the poorly water- and oil-soluble non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 (rilpivirine) as base or hydrochloride (HCl), nanosuspensions were prepared by wet milling (Elan NanoCrystal ® technology) in an aqueous carrier. Laser diffraction showed that the average particles size were (1) close to the targeted size proportionality (200–400–800 nm), with increasing distributions the larger the average particle size, and (2) were stable over 6 months. Following single-dose administration, the plasma concentration profiles showed sustained release of TMC278 over 3 months in dogs and 3 weeks in mice. On comparison of intramuscular and subcutaneous injection of 5 mg/kg (200 nm) in dogs, the subcutaneous route resulted in the most stable plasma levels (constant at 25 ng/mL for 20 days, after which levels declined slowly to 1–3 ng/mL at 3 months); 200 nm nanosuspensions achieved higher and less variable plasma concentration profiles than 400 and 800 nm nanosuspensions. In mice, the pharmacokinetic profiles after a single 20 mg/kg dose (200 nm) were similar with two different surfactants used (poloxamer 338, or d-alpha-tocopheryl polyethylene glycol 1000 succinate). In conclusion, this study provides proof-of-concept that 200-nm sized TMC278 nanosuspensions may act as long-acting injectable.

Comparison of 3 Ultrasound Methods for Quantifying Left Ventricular Systolic Function: Correlation with Disease Severity and Prognostic Value in Dogs with Mitral Valve Disease

End-systolic volume index (ESVI) is a marker of systolic function, which can be assessed by the geometric (GM, based on Teichholz formula) or 2 planimetric methods (PM, Simpson's derived and length area methods). Systolic dysfunction (SyD) may be observed in dogs with mitral valve disease (MVD) and is better assessed by PM than GM, which does not take into account the longitudinal left ventricular systolic shortening. Six healthy dogs were used to determine the variability of the tested variables (Study 1). These variables were then prospectively assessed (Study 2) in 101 small breed dogs: 77 dogs with MVD and 24 healthy controls (CD). ESVI was measured by GM and PM in awake dogs. All within- and between-day coefficients of variation were <11% (Study 1). For Study 2, a nonlinear overestimation of ESVI was observed by GM compared with PM. PM-derived ESVI was significantly increased in ISACHC class 3 dogs compared with ISACHC class 1 dogs and exerted a significant influence on cardiac events at 5 months in dogs with MVD from ISACHC classes 2 and 3 (P < .05). ESVI can be calculated by GM and PM with good repeatability and reproducibility. However, GM overestimates ESVI in a nonlinear way. Therefore, PM-derived ESVI should be preferred for the detection of SyD that is present at the late stages of the disease.

Chronic, programmed polypeptide delivery from an implanted, multireservoir microchip device

Implanted drug delivery systems are being increasingly used to realize the therapeutic potential of peptides and proteins. Here we describe the controlled pulsatile release of the polypeptide leuprolide from microchip implants over 6 months in dogs. Each microchip contains an array of discrete reservoirs from which dose delivery can be controlled by telemetry.

Evaluation of Marginal Microgaps of Two Glass-ionomer Cements (GIC) in Dogs and Sheep in vivo

The aim of the experiment was to evaluate the marginal microgaps of two ionomer cements: Kavitan Plus (Spofa Dental) and Vitremer (3M ESPE) in dog and sheep dentition in vivo. Dentitions of sheep and dogs were restored in vivo with a conventional, glass polyalkenoic, chemically activated cement Kavitan Plus with hydrophilic properties capable and with a resinmodified glass-ionomer cement Vitremer with light-induced polymerization and autopolymerization reaction of methyl metacrylate group. The parameters of glass-ionomers were evaluated in 6 groups of animals, 2 animals in each, at various time intervals (after 1, 4 and 6 months in dogs and 3, 6 and 9 months in sheep, starting from the beginning of the experiment). The restorative materials were placed to buccal surfaces of permanent teeth. At the intervals specified, under general injection anaesthesia, throughout the experiment we extracted 24 teeth from sheep and 30 from dogs. When processing the samples of dog's teeth two samples were damaged. One month after the placement, Kavitan plus restorations became loose only in one case in dogs (80% successfulness). In sheep two Kavitan Plus restorations became loose after 9 months (50% successfulness). During the experiment we observed neither cracks nor marginal discoloration in both Kavitan Plus and Vitremer restorations. Statistically significant (P = 0.04) differences were observed in the dentin of dogs receiving glass-ionomer Vitremer restorations which exhibited lower marginal microgaps. The remaining results were non- significant (ANOVA test). Fluoride ions released from GIC support the treatment of dental hard tissues. These materials could be used as definitive restorations of class A - D cavities in dogs and dental cervical caries in sheep as well as underlying layers ofcomposite and amalgam materials.

Evaluation of a single injection of a sustained-release formulation of moxidectin for prevention of experimental heartworm infection after 12 months in dogs

To evaluate the efficacy of a single injection of a sustained-release formulation of moxidectin in preventing heartworm (Dirofilaria immitis) infection for 12 months in dogs. 14 healthy dogs. Group A (nontreated control dogs; n = 6) received sterile vehicle administered SC, and group B (treated dogs; n = 6) received a sustained-release formulation of moxidectin administered SC. All dogs were housed in a heartworm-endemic area for 11.5 months, and heartworm antigen and modified Knott tests were performed monthly. All dogs (including 2 additional control dogs [group C]) were then inoculated with infective-stage larvae (L3) of D. immitis, and 4.5 months later, all dogs were euthanatized and post-mortem examinations were performed. Adult D. immitis were counted and measured, and their age was estimated. All dogs in groups A and C were infected with young (4- to 4.5-month old) adult male and female D. immitis. No dogs in group B were infected with heartworms. CONCLUSIONS AND. The age of heartworms recovered suggests that infection was the result of experimental inoculation and not natural exposure to mosquitoes during the 11.5-month period the dogs resided in a heartworm-endemic area. A single SC injection of a sustained-release formulation of moxidectin was effective in providing protection against heartworm infection after 12 months in dogs. This formulation is a convenient method of heartworm prophylaxis that could eliminate the problem of poor owner compliance.

The diagnosis and prognosis of synovial tumors in dogs: 35 cases.

Although synovial cell sarcoma is reported to be the most common neoplasm of the canine synovium, this retrospective study of 35 canine synovial tumors found that the majority were of histiocytic origin. Five (14.3%) synovial cell sarcomas were identified by positive immunohistochemical staining with antibodies to cytokeratin. Eighteen (51.4%) histiocytic sarcomas were identified by cell morphology and immunohistochemical staining with antibodies to CD18. Six (17.1%) synovial myxomas were identified by histologic pattern. The remaining six (17.1%) synovial tumors represented a variety of sarcomas, including two malignant fibrous histiocytomas (actin positive), one fibrosarcoma, one chondrosarcoma, and two undifferentiated sarcomas. Rottweilers were overrepresented in the histiocytic sarcoma category and Doberman Pinschers were overrepresented in the synovial myxoma category. The average survival time was 31.8 months for dogs with synovial cell sarcoma, 5.3 months for dogs with histiocytic sarcoma, 30.7 months for dogs with synovial myxoma, and 3.5 months for dogs with other sarcomas. Among the dogs with follow-up information available, metastatic disease was detected in 25% of dogs with synovial cell sarcoma, in 91% of dogs with histiocytic sarcoma, in none of the dogs with synovial myxoma, and in 100% of dogs with other sarcomas. Immunohistochemical staining for cytokeratin, CD18, and smooth muscle actin is recommended to make the diagnosis and thereby predict the behavior of synovial tumors in dogs.

Long-term temporal evaluation of ground reaction forces during development of experimentally induced osteoarthritis in dogs.

To describe changes in vertical ground reaction forces (GRF) over 48 months in dogs with osteoarthritis (OA) of the stifle joint induced by transection of a cranial cruciate ligament (CCL). 12 clinically normal adult dogs. Vertical GRF (eg, peak force and impulse) were determined prior to and 1, 2, 3, 6, 10, and 12 months after transection of the right CCL. In 7 dogs, data were also collected 24, 32, 38, 42, and 48 months after transection. Vertical peak force and impulse were significantly decreased in the right hind limb at all times after transection, compared with baseline values. From 10 through 48 months after transection, vertical GRF remained essentially static. Ground reaction forces in the unoperated (left) hind limb also changed significantly during the study. Left vertical impulse significantly increased 3 months after transection, whereas at 24, 38, 42, and 48 months after transection, left vertical peak force was significantly decreased, compared with the baseline value. Mean intradog coefficients of variation (CV) for peak vertical force and impulse ranged from 738 and 9.32, respectively, 1 month after transection to 1.96 and 2.76, respectively, at 42 months. Vertical GRF in the affected hind limb equilibrated approximately 10 months after CCL transection. Prior to this, force transmission across the affected stifle joint changed significantly over time. Intradog CV were small, indicating that GRF may be an appropriate outcome measurement for evaluation of OA development induced by CCL transection in dogs.

Retrobulbar tumors in dogs and cats: 25 cases.

Twenty-five cases of retrobulbar tumors are presented and discussed. Affected animals were dogs and cats (average 10.7 years). No breed or sex predisposition was noted. The most common clinical signs were exophthalmos (84%), conjunctival hyperemia (40%), protrusion of the nictitating membrane (28%), exposure keratitis (20%) and fundus abnormalities (20%). Diagnostic tools included fine needle aspiration, radiography, ultrasonography, computed tomography and histology. Surgical treatment by orbitotomy or exenteration was combined with chemotherapy and radiotherapy in some cases. The prognosis was poor with low survival times: 1 month in cats, and 10 months in dogs, with a high rate of euthanasia (35%) at the time of diagnosis.

The influences of molar intrusion on the inferior alveolar neurovascular bundle and root using the skeletal anchorage system in dogs.

The skeletal anchorage system (SAS) was developed as intraoral rigid anchors for open-bite correction by intrusion of molars. Since the application of SAS is a new modality in orthodontic treatment, the influences of radical molar intrusion on the root and the inferior alveolar neurovascular bundle were unknown. The purpose of this research is to verify the effect of molar intrusion on the neurovascular bundle, the level of osseointegration of bone screws, and root resorption. The results of this study showed mandibular molars were intruded 3.4 mm on the average over 7 months in dogs. The miniplates were well stabilized with osseointegrated bone screws and the peri-implant soft tissues showed slight inflammatory changes. Neither nerves nor blood vessels were damaged. Root resorption was observed but was repaired with new cementum. We concluded that the SAS utilizing transmucosal titanium miniplates as an immovable orthodontic anchorage could provide a new modality for molar intrusions without serious iatrogenic problems.