Surgical management of unilateral restrictive strabismus in an 8-month-old dog.

CASE HISTORY: An 8-month-old male, entire, mixed-breed dog was presented with a 1-month history of left exophthalmos and green mucopurulent ocular discharge. Subsequently, exophthalmos resolved but esotropia (medial strabismus) developed in the left eye, prompting referral to an ophthalmologist. CLINICAL FINDINGS: At the initial referral consultation, enophthalmos and esotropia of the left eye were identified. The patient showed mild improvement after a 3-week tapering course of oral prednisolone and doxycycline. MRI was performed and showed left medial rectus muscle atrophy with increased contrast enhancement which was consistent with chronic extraocular muscle myositis (EOM). A forced duction test was performed to confirm the diagnosis of fibrosing esotropia, which is likely a sequela of chronic EOM. DIAGNOSIS: Fibrosing esotropia presumably caused by untreated EOM. TREATMENT AND OUTCOME: One month later, esotropia progressed to a marked ventro-medial strabismus resulting in visual deprivation. Surgical release of the ventral oblique, medial and ventral recti muscles was performed, resulting in immediate resolution of the enophthalmos. Despite a tapering post-operative course of oral prednisolone, mild esotropia was present 4 weeks later. In an effort to stabilise the globe position, the low dose of prednisolone was increased to a higher anti-inflammatory dose before slowly tapering over 2 months. The vision in the left eye was improved after surgery and has been maintained since without further treatment. CLINICAL RELEVANCE: This is the first documented case of fibrosing esotropia in a young dog with prior signs of acute exophthalmos. Fibrosing esotropia has been documented in certain breeds or as a sequela to chronic EOM. In this patient, it was presumably caused by EOM, which was strongly supported by the case history, progression and MRI findings. Most historical reports of EOM described it as a bilateral condition that resolves with systemic corticosteroids at an anti-inflammatory dose. EOM has been shown to also present unilaterally and it can progress to strabismus if not promptly recognised and treated with systemic steroids. Surgical management can restore vision when severe strabismus results in visual deprivation.

Implicating SCF complexes in organogenesis in Caenorhabditis elegans.

Development of the Caenorhabditis elegans foregut (pharynx) is regulated by a network of proteins that includes the Retinoblastoma protein (pRb) ortholog LIN-35; the ubiquitin pathway components UBC-18 and ARI-1; and PHA-1, a cytoplasmic protein. Loss of pha-1 activity impairs pharyngeal development and body morphogenesis, leading to embryonic arrest. We have used a genetic suppressor approach to dissect this complex pathway. The lethality of pha-1 mutants is suppressed by loss-of-function mutations in sup-35/ztf-21 and sup-37/ztf-12, which encode Zn-finger proteins, and by mutations in sup-36. Here we show that sup-36 encodes a divergent Skp1 family member that binds to several F-box proteins and the microtubule-associated protein PLT-1/τ. Like SUP-35, SUP-36 levels were negatively regulated by UBC-18-ARI-1. We also found that SUP-35 and SUP-37 physically associated and that SUP-35 could bind microtubules. Thus, SUP-35, SUP-36, and SUP-37 may function within a pathway or complex that includes cytoskeletal components. Additionally, SUP-36 may regulate the subcellular localization of SUP-35 during embryogenesis. We carried out a genome-wide RNAi screen to identify additional regulators of this network and identified 39 genes, most of which are associated with transcriptional regulation. Twenty-three of these genes acted via the LIN-35 pathway. In addition, several S-phase kinase-associated protein (Skp)1-Cullin-F-Box (SCF) components were identified, further implicating SCF complexes as part of the greater network controlling pharyngeal development.

A regulatory module controlling pharyngeal development and function in Caenorhabditis elegans.

In Caenorhabditis elegans, the differentiation and morphogenesis of the foregut are controlled by several transcriptional regulators and cell signaling events, and by PHA-1, an essential cytoplasmic protein of unknown function. Previously we have shown that LIN-35 and UBC-18-ARI-1 contribute to the regulation of pha-1 and pharyngeal development through the Zn-finger protein SUP-35/ZTF-21. Here we characterize SUP-37/ZTF-12 as an additional component of the PHA-1 network regulating pharyngeal development. SUP-37 is encoded by four distinct splice isoforms, which contain up to seven C2H2 Zn-finger domains, and is localized to the nucleus, suggesting a role in transcription. Similar to sup-35, sup-37 loss-of-function mutations can suppress both LOF mutations in pha-1 as well as synthetic-lethal double mutants, including lin-35; ubc-18, which are defective in pharyngeal development. Genetic, molecular, and expression data further indicate that SUP-37 and SUP-35 may act at a common step to control pharyngeal morphogenesis, in part through the transcriptional regulation of pha-1. Moreover, we find that SUP-35 and SUP-37 effect pharyngeal development through a mechanism that can genetically bypass the requirement for pha-1 activity. Unlike SUP-35, SUP-37 expression is not regulated by either the LIN-35 or UBC-18-ARI-1 pathways. In addition, SUP-37 carries out two essential functions that are distinct from its role in regulating pharyngeal development with SUP-35. SUP-37 is required within a subset of pharyngeal muscle cells to facilitate coordinated rhythmic pumping and in the somatic gonad to promote ovulation. These latter observations suggest that SUP-37 may be required for the orchestrated contraction of muscle cells within several tissues.

A network of genes antagonistic to the LIN-35 retinoblastoma protein of Caenorhabditis elegans.

The Caenorhabditis elegans pRb ortholog, LIN-35, functions in a wide range of cellular and developmental processes. This includes a role of LIN-35 in nutrient utilization by the intestine, which it carries out redundantly with SLR-2, a zinc-finger protein. This and other redundant functions of LIN-35 were identified in genetic screens for mutations that display synthetic phenotypes in conjunction with loss of lin-35. To explore the intestinal role of LIN-35, we conducted a genome-wide RNA-interference-feeding screen for suppressors of lin-35; slr-2 early larval arrest. Of the 26 suppressors identified, 17 fall into three functional classes: (1) ribosome biogenesis genes, (2) mitochondrial prohibitins, and (3) chromatin regulators. Further characterization indicates that different categories of suppressors act through distinct molecular mechanisms. We also tested lin-35; slr-2 suppressors, as well as suppressors of the synthetic multivulval phenotype, to determine the spectrum of lin-35-synthetic phenotypes that could be suppressed following inhibition of these genes. We identified 19 genes, most of which are evolutionarily conserved, that can suppress multiple unrelated lin-35-synthetic phenotypes. Our study reveals a network of genes broadly antagonistic to LIN-35 as well as genes specific to the role of LIN-35 in intestinal and vulval development. Suppressors of multiple lin-35 phenotypes may be candidate targets for anticancer therapies. Moreover, screening for suppressors of phenotypically distinct synthetic interactions, which share a common altered gene, may prove to be a novel and effective approach for identifying genes whose activities are most directly relevant to the core functions of the shared gene.

The platelet-surface thiol isomerase enzyme ERp57 modulates platelet function.

BACKGROUND: Thiol isomerases are a family of endoplasmic reticulum enzymes which orchestrate redox-based modifications of protein disulphide bonds. Previous studies have identified important roles for the thiol isomerases PDI and ERp5 in the regulation of normal platelet function. AIM: Recently, we demonstrated the presence of a further five thiol isomerases at the platelet surface. In this report we aim to report the role of one of these enzymes - ERp57 in the regulation of platelet function. METHODS/RESULTS: Using enzyme activity function blocking antibodies, we demonstrate a role for ERp57 in platelet aggregation, dense granule secretion, fibrinogen binding, calcium mobilisation and thrombus formation under arterial conditions. In addition to the effects of ERp57 on isolated platelets, we observe the presence of ERp57 in the developing thrombus in vivo. Furthermore the inhibition of ERp57 function was found to reduce laser-injury induced arterial thrombus formation in a murine model of thrombosis. CONCLUSIONS: These data suggest that ERp57 is important for normal platelet function and opens up the possibility that the regulation of platelet function by a range of cell surface thiol isomerases may represent a broad paradigm for the regulation of haemostasis and thrombosis.

Future innovations in anti-platelet therapies.

Platelets have long been recognized to be of central importance in haemostasis, but their participation in pathological conditions such as thrombosis, atherosclerosis and inflammation is now also well established. The platelet has therefore become a key target in therapies to combat cardiovascular disease. Anti-platelet therapies are used widely, but current approaches lack efficacy in a proportion of patients, and are associated with side effects including problem bleeding. In the last decade, substantial progress has been made in understanding the regulation of platelet function, including the characterization of new ligands, platelet-specific receptors and cell signalling pathways. It is anticipated this progress will impact positively on the future innovations towards more effective and safer anti-platelet agents. In this review, the mechanisms of platelet regulation and current anti-platelet therapies are introduced, and strong, and some more speculative, potential candidate target molecules for future anti-platelet drug development are discussed.

IPSE/alpha-1: a major immunogenic component secreted from Schistosoma mansoni eggs.

During infection with Schistosoma mansoni the egg stage of this parasite modulates the initial T helper (Th1) response into a Th2 response. This suggests that schistosome eggs contain factors responsible for that effect. We have recently described a glycoprotein (IPSE) from S. mansoni eggs that has a potent IL-4-inducing effect on human basophils. Here we demonstrate that IPSE is identical to a previously described molecule, the S. mansoni egg antigen alpha-1. We furthermore show that the expression of IPSE/alpha-1 at the level of both mRNA and protein is restricted to the egg stage. IPSE/alpha-1 is produced in and released from the subshell area of the egg and comes into close contact with inflammatory cells recruited to the vicinity of the egg surface. In line with this IPSE/alpha-1 is one of three major S. mansoni egg glycoproteins that induce pronounced antibody responses. Its IL-4-inducing capacity, moreover, suggests that IPSE/alpha-1 plays a role in initiating the Th2 response induced by patent S. mansoni infections.

The use of transscleral cyclophotocoagulation with a diode laser for the treatment of glaucoma occurring post intracapsular extraction of displaced lenses: a retrospective study of 15 dogs (1995-2000).

The objective of this retrospective study was to evaluate transscleral cyclophotocoagulation (TSCP) using a diode laser for treating aphakic glaucoma that developed after intracapsular lens extraction (ICLE) had been performed for displaced lenses. Records of 15 dogs (21 eyes) were reviewed. The intraocular pressure (IOP) and the presence of vision were recorded at the time of ICLE and TSCP and at 1, 3, 6-9, 12 and 24 months post TSCP. The glaucoma was considered controlled if the IOP was less than 25 mmHg. The results indicated that the effectiveness of TSCP using a diode laser for treating aphakic glaucoma was of a short-term duration (1-3 months), with three patients needing repeat TSPC. In addition, adjunctive antiglaucoma medications were often required to maintain an adequately controlled IOP. Over the 24-month period the number of dogs requiring intrascleral prosthesis, intraocular gentamicin or enucleation, or that were lost to follow-up, increased.

Immune-dependent thrombocytopaenia in mice infected with Schistosoma mansoni.

As has been shown previously, immunologically intact mice with patent Schistosoma mansoni infections had a significantly lower mean platelet number than intact uninfected mice (P<0.0001). However, platelet numbers in T-cell deprived mice with patent infections were not significantly different from those in uninfected T-cell deprived mice. Also, platelet counts in both the infected and uninfected T-cell deprived groups were not significantly different from those in intact uninfected mice. The S. mansoni-induced thrombocytopaenia in mice is thus seemingly immune dependent. Immunologically intact mice with chronic 12-week-old S. mansoni infections had IgG antibodies that were reactive in an ELISA-type assay with whole fixed platelets of both mouse and human origin. In Western immunoblots the IgG antibodies from chronically-infected mice reacted in particular against mouse and human platelet antigens of 90, 37 and 30 kDa. Antisera raised from 2 rabbits, immunized respectively with mouse and human platelet antigens, cross-reacted with antigens of the larval, adult worm and egg stages of S. mansoni. These results support the hypothesis that an anti-platelet antibody response may be the cause of the thrombocytopaenia observed in mice with patent schistosome infections.

Identification of a fibrinolytic enzyme in Schistosoma mansoni eggs and modulated blood fibrinogen metabolism in S. mansoni-infected mice.

Aqueous extracts of Schistosoma mansoni eggs have been shown to have fibrinolytic activity inhibitable by a serine protease inhibitor. Fibrinolytic activity was not present in extracts of either adult worms or cercariae. A 27 kDa enzyme that was proteolytically active on fibrinogen in zymography and that degraded fibrinogen in a pattern similar to that of plasmin, is presumed to be responsible for the schistosome egg fibrinolytic activity. Anti-human fibrinogen antisera were shown to have antibodies that cross-reacted with mouse fibrinogen in Western immunoblots. Electroblotted sera from S. mansoni-infected and control uninfected mice displayed different antigenic profiles when probed with the cross-reactive anti-human fibrinogen antibodies, suggesting an alteration in mouse host fibrinogen metabolism as a result of the parasitic infection. We discuss the possibility that modulation of fibrinogen metabolism is a factor in a recently discovered anti-atherogenic effect exerted by schistosomes.

An anti-atherogenic effect of Schistosoma mansoni infections in mice associated with a parasite-induced lowering of blood total cholesterol.

In affluent societies the prevalences of so-called 'Western' diseases such as atherosclerosis, allergies and autoimmune disorders appear to have increased, while many diseases caused by communicable infections are now relatively less common. To test whether there may be a causal relationship we examined the effects of Schistosoma mansoni infections in mice that develop cardiovascular pathology as a result of a genetic deficiency in apolipoprotein E (apoE-/-). The development of atherosclerotic lesions in the aortic arch and brachiocephalic artery of the apoE-/- mice was reduced by approximately 50% in mice with the parasitic infection, when comparison was made with uninfected control mice fed the same diet. Observations on S. mansoni-infected conventional laboratory mice indicate that patent schistosome infections could be counteracting the effects of an atherogenic diet by modulating host lipid metabolism and inducing a reduction in blood total cholesterol concentrations.

Diode laser transscleral cyclophotocoagulation for the treatment of primary glaucoma in 18 dogs: a retrospective study.

OBJECTIVE: To evaluate a higher total energy protocol for diode laser transscleral cyclophotocoagulation (TSCP) for the treatment of primary glaucoma in dogs. PROCEDURES: Diode laser TSCP was performed on 24 eyes of 18 dogs (six dogs were treated bilaterally). A glaucoma probe with a spot size of 600 microns was applied in 25 sites 3-4 mm posterior to the limbus for dogs. A power of 1000 milliwatts (mW) for a duration of 5000 milliseconds (ms) to deliver an average 125 J of energy per eye, which is higher energy delivery than previously reported for the diode laser for the treatment of canine glaucoma. Anterior chamber needle paracentesis was performed using a 30-gauge needle until intraocular pressure (IOP) was measured to be less than 15 mmHg by applanation tonometry. Subconjunctival corticosteroids were administered in all cases and a temporary tarsorrhaphy was applied in 13 of the 24 treated eyes. Postoperative topical and systemic corticosteroids, and carbonic anhydrase inhibitors were administered as required to maintain an IOP of less than 25 mmHg. Intraocular pressure was measured at approximately 3 h postoperatively then at 1, 2, 3, 7, 14, 28, 60, 120, and 180 days. Adequate control of IOP was considered to be less than 25 mmHg on re-examination. RESULTS: Intraocular pressure was successfully maintained within the normal range in 22/24 eyes (92%). Three eyes required a second diode laser treatment within the first week postoperatively. Two eyes developed recurrence of glaucoma at 8 and 32 weeks postoperatively. Follow-up ranged from 8 to 21 months. Fourteen eyes were assessed by clinical examination and history to be potentially visual. Of these, seven eyes (50%) regained useful visual function. Mean IOP at 6 months was 11.0 +/- 7.6 mmHg and at 12 months was 11.0 +/- 8 mmHg. Postoperative complications included cataracts (six cases), corneal ulceration (three cases), and keratitis (three cases). Of 13 cases that were treated postoperatively with a temporary tarsorrhaphy, only one case (8%) developed corneal disease. Of the remaining 11 cases that were not treated with a temporary tarsorrhaphy, there were three cases of corneal ulceration and two cases of vascular keratitis (45% incidence of corneal disease). This was found to be statistically significant (P < 0.05). Postoperative complications of hyphema and phthisis bulbi were not seen in this series. CONCLUSION: Low energy, higher power laser cyclophotocoagulation was effective in the treatment of canine primary glaucoma, with 50% of potentially visual eyes regaining vision, but may cause an increased incidence of secondary cataracts.

Lateral canthoplasty for facial nerve paralysis and exposure keratitis in a mouse.

An 11-month old entire male mouse was presented with mucopurulent discharge and corneal scarring of the left eye. This mouse previously had a history of ear mites that responded to therapy, and had undergone surgery to remove a large discharging mass from the left side of the neck. The eye problem was noted prior to surgery, but after the ear mite infection. Examination revealed absence of a palpebral reflex in the left eye, and no spontaneous movements of the left ear or lip and whiskers. Examination of the left eye revealed extensive corneal vascularisation and pigmentation. Intraocular structures were not visible. A diagnosis of facial nerve paralysis and secondary exposure keratitis was made. Surgery was performed to close the lateral canthus and reduce corneal exposure. Following surgery the eye discharge ceased and corneal vascularisation resolved, however corneal pigmentation persisted.

Results of grid keratotomy, superficial keratectomy and debridement for the management of persistent corneal erosions in 92 dogs.

Ninety-two cases of persistent corneal erosions in dogs were analyzed for breed, gender, age and which eye was affected. The results of the treatment of 92 persistent corneal erosions in dogs by superficial keratectomy (SK), grid keratotomy (GK), or debridement with a sterile dry cotton swab are presented. These techniques gave better rates of healing than have been previously reported. All cases of persistent corneal erosions healed in this study. However, it must be noted that three cases treated with debridement only failed to heal after several treatments and were eventually treated with SK. After one procedure 80 out of 92 (87%) had healed. After one procedure, 63% of cases treated with debridement healed, 100% of cases treated with SK healed, and 85% of cases treated with GK healed. At the first postoperative visit, 88% (21/24 cases) of ulcers treated by SK had healed, and 75% (39/52 cases) of ulcers treated by GK had healed. Only 25% of the persistent corneal erosions had healed at the first visit after debridement. All 24 cases of persistent corneal erosions treated with SK healed after one treatment in a mean +/- SD of 9.3 +/- 3.9 days (median of 7 days). Fifty-two cases were managed with GK; 44 (83%) of these healed with one procedure and eight cases required a second GK procedure to resolve. A mean +/- SD of 13.4 +/- 5.1 days (median of 11.5 days) following GK was required for the persistent corneal erosions to heal. Nineteen cases were initially managed by debridement with a dry cotton swab under local anesthesia. Sixteen out of these 19 debridement cases healed (giving an overall healing rate of 84%) in a mean +/- SD time of 23.4 +/- 11.1 days (median 21.5). There were three cases that did not heal with debridement. These cases were debrided at 10-20 day intervals for 30-60 days, and were then treated with SK. Two of these cases healed within 7 days, the other case required 18 days to heal. Sixty-three per cent of persistent corneal erosions treated with debridement healed after one procedure; however, only four out of 19 cases (21%) were healed at the first revisit. Complications were rare: corneal edema occurred in two cases following multiple GK, and excessive granulation tissue in one case was managed with a SK. There was the occurrence of an ulcer adjacent to the surgery site in four cases, two cases following GK and two cases following SK.

Modification of the orbital rim anchorage method for surgical replacement of the gland of the third eyelid in dogs.

Excision of a prolapsed gland of the third eyelid predisposes a dog to develop keratoconjunctivitis sicca later in its lifetime, and replacement, rather than excision, of the gland is the preferred method of treatment. One method of gland replacement involves suturing the prolapsed gland to the periosteum of the ventral orbital rim. As originally described, however, the procedure required that the surgeon make a U-turn with the needle and suture within the confines of the ventral fornix. This report describes modifications to the original technique that eliminate this difficult step and make it easier for the surgeon to obtain a secure bite of the orbital periosteum.

Eye diseases in Siberian husky dogs.

A full ophthalmic examination was performed on 40 Siberian husky dogs using direct and indirect ophthalmoscopy, gonloscopy and nasolacrimal cannulation. Eight (20%) of the dogs were found to have distichia, 10 (25%) had excessive medial caruncular hairs, 8 (20%) had absence, displacement, or narrowing of the nasolacrimal puncta, 2 (5%) had bilateral corneal crystalline opacities, and 2 (5%) had unilateral areas of lateral corneal lipidosis. Fifty percent of the dogs had some abnormality of the iridocorneal (drainage) angle. However, in only one of these was the deformity severe enough to require glaucoma prophylaxis. An association between blue iris colour and malformation of the iridocorneal angle was noted.

Superficial stromal keratitis in the dog.

Superficial stromal keratitis or pannus is a syndrome of corneal, conjunctival and third eyelid inflammation. Superficial stromal keratitis mainly presents as a subepithelial corneal infiltration of vascular connective tissue, and usually arises from the lateral (temporal) limbal area. In some dogs perilimbal hyperaemia and third eyelid blepharitis can be present without corneal involvement. The most commonly affected breed of dog is the German Shepherd. Most cases of superficial stromal keratitis can be controlled with topical corticosteroids, and only rarely is cryosurgery or superficial keratectomy required to remove excessive pigment and or granulation tissue. The precise aetiology of SSK is unknown, but is likely to be multifactorial, with sunlight being a significant factor. Corneal lipidosis and keratoconjunctivitis sicca can occur secondary to superficial stromal keratitis.