Mesenteric lymphatic vessels adapt to mesenteric venous hypertension by becoming weaker pumps.

Lymphangions, the segments of lymphatic vessels between two adjacent lymphatic valves, actively pump lymph. Acute changes in transmural pressure and lymph flow have profound effects on lymphatic pump function in vitro. Chronic changes in pressure and flow in vivo have also been reported to lead to significant changes in lymphangion function. Because changes in pressure and flow are both cause and effect of adaptive processes, characterizing adaptation requires a more fundamental analysis of lymphatic muscle properties. Therefore, the purpose of the present work was to use an intact lymphangion isovolumetric preparation to evaluate changes in mesenteric lymphatic muscle mechanical properties and the intracellular Ca(2+) in response to sustained mesenteric venous hypertension. Bovine mesenteric veins were surgically occluded to create mesenteric venous hypertension. Postnodal mesenteric lymphatic vessels from mesenteric venous hypertension (MVH; n = 6) and sham surgery (Sham; n = 6) animals were isolated and evaluated 3 days after the surgery. Spontaneously contracting MVH vessels generated end-systolic active tension and end-diastolic active tension lower than the Sham vessels. Furthermore, steady-state active tension and intracellular Ca(2+) concentration levels in response to KCl stimulation were also significantly lower in MVH vessels compared with those of the Sham vessels. There was no significant difference in passive tension in lymphatic vessels from the two groups. Taken together, these results suggest that following 3 days of mesenteric venous hypertension, postnodal mesenteric lymphatic vessels adapt to become weaker pumps with decreased cytosolic Ca(2+) concentration.

Adaptation of mesenteric lymphatic vessels to prolonged changes in transmural pressure.

In vitro studies have revealed that acute increases in transmural pressure increase lymphatic vessel contractile function. However, adaptive responses to prolonged changes in transmural pressure in vivo have not been reported. Therefore, we developed a novel bovine mesenteric lymphatic partial constriction model to test the hypothesis that lymphatic vessels exposed to higher transmural pressures adapt functionally to become stronger pumps than vessels exposed to lower transmural pressures. Postnodal mesenteric lymphatic vessels were partially constricted for 3 days. On postoperative day 3, constricted vessels were isolated, and divided into upstream (UP) and downstream (DN) segment groups, and instrumented in an isolated bath. Although there were no differences between the passive diameters of the two groups, both diastolic diameter and systolic diameter were significantly larger in the UP group than in the DN group. The pump index of the UP group was also higher than that in the DN group. In conclusion, this is the first work to report how lymphatic vessels adapt to prolonged changes in transmural pressure in vivo. Our results suggest that vessel segments upstream of the constriction adapt to become both better fluid conduits and lymphatic pumps than downstream segments.

Evaluation of gravimetric techniques to estimate the microvascular filtration coefficient.

Microvascular permeability to water is characterized by the microvascular filtration coefficient (K(f)). Conventional gravimetric techniques to estimate K(f) rely on data obtained from either transient or steady-state increases in organ weight in response to increases in microvascular pressure. Both techniques result in considerably different estimates and neither account for interstitial fluid storage and lymphatic return. We therefore developed a theoretical framework to evaluate K(f) estimation techniques by 1) comparing conventional techniques to a novel technique that includes effects of interstitial fluid storage and lymphatic return, 2) evaluating the ability of conventional techniques to reproduce K(f) from simulated gravimetric data generated by a realistic interstitial fluid balance model, 3) analyzing new data collected from rat intestine, and 4) analyzing previously reported data. These approaches revealed that the steady-state gravimetric technique yields estimates that are not directly related to K(f) and are in some cases directly proportional to interstitial compliance. However, the transient gravimetric technique yields accurate estimates in some organs, because the typical experimental duration minimizes the effects of interstitial fluid storage and lymphatic return. Furthermore, our analytical framework reveals that the supposed requirement of tying off all draining lymphatic vessels for the transient technique is unnecessary. Finally, our numerical simulations indicate that our comprehensive technique accurately reproduces the value of K(f) in all organs, is not confounded by interstitial storage and lymphatic return, and provides corroboration of the estimate from the transient technique.

Balance point characterization of interstitial fluid volume regulation.

The individual processes involved in interstitial fluid volume and protein regulation (microvascular filtration, lymphatic return, and interstitial storage) are relatively simple, yet their interaction is exceedingly complex. There is a notable lack of a first-order, algebraic formula that relates interstitial fluid pressure and protein to critical parameters commonly used to characterize the movement of interstitial fluid and protein. Therefore, the purpose of the present study is to develop a simple, transparent, and general algebraic approach that predicts interstitial fluid pressure (P(i)) and protein concentrations (C(i)) that takes into consideration all three processes. Eight standard equations characterizing fluid and protein flux were solved simultaneously to yield algebraic equations for P(i) and C(i) as functions of parameters characterizing microvascular, interstitial, and lymphatic function. Equilibrium values of P(i) and C(i) arise as balance points from the graphical intersection of transmicrovascular and lymph flows (analogous to Guyton's classical cardiac output-venous return curves). This approach goes beyond describing interstitial fluid balance in terms of conservation of mass by introducing the concept of inflow and outflow resistances. Algebraic solutions demonstrate that P(i) and C(i) result from a ratio of the microvascular filtration coefficient (1/inflow resistance) and effective lymphatic resistance (outflow resistance), and P(i) is unaffected by interstitial compliance. These simple algebraic solutions predict P(i) and C(i) that are consistent with reported measurements. The present work therefore presents a simple, transparent, and general balance point characterization of interstitial fluid balance resulting from the interaction of microvascular, interstitial, and lymphatic function.

Intraocular pressure response to topically administered fluorometholone.

Certain corticosteroids, including fluorometholone, have been reported to have a low propensity for elevating intraocular pressure. Our clinical impression was that the incidence of IOP increase with fluorometholone may be higher than reported. This study was to determine the incidence and degree of IOP response to 0.1% fluorometholone suspension in 43 patients demonstrated to be responsive to 0.1% dexamethasone sodium phosphate solution. Twenty-six patients (60.5%) had IOP increases of 5 mm Hg or more while receiving fluorometholone, and three patients (7%) demonstrated pressure rises greater than 15 mm Hg. Fluorometholone can significantly raise IOP in a significant number of corticosteroid responders.

Betaxolol vs timolol. A six-month double-blind comparison.

Betaxolol hydrochloride (0.5%) and timolol maleate (0.5%) were compared in a six-month randomized, double-blind study involving 29 patients with glaucoma. The two drugs were comparable with regard to efficacy in lowering intraocular pressure. Betaxolol effected an average reduction of 7.6 mm Hg (26%); timolol, 8.4 mm Hg (29%). No patient required adjunctive medications during this study. Ocular side effects were mild and similar for both treatments. Neither drug affected corneal sensitivity, visual acuity, basal tear production, or pupil size. Since betaxolol has been shown to have little effect on the cardiopulmonary system, it should be strongly considered for the treatment of glaucoma.

A 90-day study of the efficacy and side effects of 0.25% and 0.5% apraclonidine vs 0.5% timolol. Apraclonidine Primary Therapy Study Group.

OBJECTIVE: To compare long-term intraocular pressure (IOP)-lowering efficacy of 0.25% and 0.5% apraclonidine hydrochloride with 0.5% timolol maleate. DESIGN: Multicenter, randomized, double-masked trial. Adult patients of either sex diagnosed as having open-angle glaucoma or ocular hypertension were enrolled following appropriate washout from all ocular hypotensive medications. Morning IOPs of 22 to 35 mm Hg were required for entry. Patients received 0.25% or 0.5% apraclonidine 3 times a day or 0.5% timolol twice a day for 90 days. Intraocular pressure was measured at 8 AM (before morning dosing) and at 4 PM (8 hours after dosing) on days 1, 30, and 90, and only at 8 AM on day 14. RESULTS: All 3 medications significantly reduced IOP from baseline at all observation times (P < .001): 0.5% apraclonidine reduced IOP more than 0.25% apraclonidine; no significant difference was observed between 0.5% apraclonidine and 0.5% timolol 8 hours after dosing on days 1, 30, and 90; and a significant difference (P < .05) in favour of 0.5% timolol over 0.25% apraclonidine was observed 8 hours after dosing on day 30. At all morning visits following evening dosing, 0.5% timolol significantly reduced IOP more than both concentrations of apraclonidine. CONCLUSIONS: Both 0.25% and 0.5% apraclonidine significantly reduce IOP when used as primary ocular hypotensive medication. Although 0.25% and 0.5% apraclonidine reduce IOP to a similar degree as 0.5% timolol 8 hours after morning dosing, neither concentration is as effective for reducing morning IOP after evening dosing.

Reduction of pupillary constriction during cataract surgery using suprofen.

The efficacy of a new nonsteroidal anti-inflammatory agent, suprofen, for reducing pupillary constriction during cataract surgery was ascertained in a double-masked, multicenter, clinical study. Prior to surgery 1.0% suprofen or a placebo was instilled; the surgeon's normal regimen of mydriatics and cycloplegics was used. Suprofen (209 patients) was far more effective than the placebo (203 patients) in maintaining a dilated pupil prior to intraocular lens (IOL) implantation (or instillation of a miotic). The mean pupillary area prior to IOL implantation was 6.3 sq mm larger (20% larger) in patients treated with suprofen than in patients receiving the placebo. The investigators' subjective evaluations of the adequacy of pupil size for IOL implantation and of the difficulty of IOL implantation favored patients treated with suprofen over those receiving the placebo.

Prevention of the rise in intraocular pressure following neodymium-YAG posterior capsulotomy using topical 1% apraclonidine.

We studied apraclonidine hydrochloride (aplonidine hydrochloride or ALO 2145), an alpha-agonist, for its effect on the intraocular pressure (IOP) rise following neodymium-YAG posterior capsulotomy (YPC). In a prospective multicentered double-masked study, 63 eyes were pretreated with one drop of either 1% apraclonidine hydrochloride or placebo one hour before performing YPC and again following the laser treatment. The greatest IOP rise in the placebo-treated eyes occurred in the third hour after YPC, when the mean (+/- SD) IOP rose from a baseline pressure of 16.4 +/- 3.7 to 20.8 +/- 6.8 mm Hg. In apraclonidine-treated eyes, the IOP fell from a mean of 15.6 +/- 3.8 to 12.8 +/- 6.0 mm Hg three hours postoperatively. There were five times as many eyes that had an IOP rise greater than 10 mm Hg in the placebo-treated group compared with those treated with apraclonidine. Apraclonidine proved to be highly effective in preventing the rise in IOP following YPC.

Evaluation of dexamethasone acetate as a topical ophthalmic formulation.

Penetration of an ophthalmic suspension of 0.1% dexamethasone acetate into the rabbit cornea and aqueous humor was unaffected by the status of the corneal epithelium or by the presence or absence of intraocular inflammation. However, the total quantity of this corticosteroid that could be measured in the cornea or aqueous humor was significantly less than that produced by either dexamethason alcohol or dexamethasone sodium phosphate. Despite this, dexamethasone acetate was the most effective of the three dexamethasone derivatives in suppressing inflammation in the cornea, which indicates that following topical administration to the eye it is the most potent of the dexamethasone derivatives studied. This greater therapeutic effect does not seem to be accompanied by a greater propensity to increase intraocular pressure. Comparison of the intraocular pressureincreasing effect in known corticosteroid responders of dexamethasone acetate with that of dexamethasone sodium phosphate, the least effective of the dexamethasone products studied, demonstrated no difference between the two drugs. These data support the conclusion that dexamethasone acetate is superior to the commercially available dexamethasone derivatives for use as a topical ocular anti-inflammatory agent.

A double-masked three-month comparison between 0.25% betaxolol suspension and 0.5% betaxolol ophthalmic solution.

In 352 patients with primary open-angle glaucoma or ocular hypertension, a multicenter double-masked, parallel-group clinical study compared the effects on intraocular pressure and ocular comfort of 0.5% betaxolol ophthalmic solution, a cardioselective beta-adrenergic blocking agent, with 0.25% betaxolol suspension. With twice-daily dosages, baseline intraocular pressure was significantly reduced (P = .0005), with no significant difference between the two groups, at Week 2 and at Months 1, 2, and 3. Further, the prevalence of ocular discomfort upon topical instillation was significantly lower for 0.25% betaxolol suspension than for 0.5% betaxolol solution (P = .0005).

Glare testing in cataract patients: instrument evaluation and identification of sources of methodological error.

This study sought to determine the relative sensitivity of two commercially available glare testers in predicting outdoor acuity in a population of patients with minimal cataracts. Two target optotypes were evaluated: high contrast letters and varying contrast sinusoidal gratings. Although both instruments demonstrated a significant correlation between indoor and outdoor acuity, they showed a significant difference between predicted outdoor acuity and obtained visual acuity. The brightness acuity tester on high intensity was inaccurate in predicting outdoor vision regardless of test optotype, overpredicting glare disability in 76% (average) of the study population. Glare disability overpredictions fell to 8% on the medium setting with +/- 2 lines of vision classified as "no change." Using the same criterion, the Miller-Nadler glare tester overpredicted glare disability in 2% of the cataract population but underpredicted glare disability in 62%. In this study, letter optotypes resulted in less variability than sinusoidal grating stimuli. In addition, we identify several methodological factors to consider before designing a glare experiment. These potential sources of error can influence the outcome of any glare study that compares indoor and outdoor acuity and include the study population, visual stimuli (optotypes), and elements of the outdoor testing situation.

Periocular cutaneous pigmentary changes associated with topical betaxolol.

PURPOSE: We report two cases of periocular cutaneous hypopigmentation and one case of hyperpigmentation which appeared while the patients were on betaxolol. We propose several possible explanations for this phenomenon. METHODS: Charts of three patients with glaucoma who developed periocular cutaneous pigmentary changes while on betaxolol were reviewed retrospectively. RESULTS: Case #1 was a 47-year-old black man with primary open angle glaucoma, started on betaxolol 0.5% in both eyes in January 1981. Bilateral hypopigmentation of the eyelids was first documented in October 1987. Betaxolol was discontinued in November 1987. In December 1990 the pigmentation had returned to normal. Case #2 was a 4-month-old white boy with unilateral primary infantile glaucoma who was started in September 1992 on betaxolol 0.25% in the left eye. Left lower eyelid hypopigmentation was seen in April 1993. Betaxolol was discontinued in July 1993. Since that time the pigmentation has returned to normal. Case #3 was a 75-year-old black man with primary open angle glaucoma. He was placed on betaxolol 0.5% in both eyes in 1987 and in March 1988 hyperpigmentation of the eyelids was seen bilaterally. Betaxolol was discontinued, and by December 1990 the pigmentation had returned to normal. CONCLUSION: These three case histories suggest that the periocular cutaneous changes described herein are secondary to local instillation of betaxolol.

Carteolol hydrochloride: controlled evaluations of its ocular hypotensive efficacy relative to its vehicle, and, in combination with pilocarpine, relative to timolol.

Carteolol is a noncardioselective beta-adrenoceptor antagonist with intrinsic sympathomimetic activity. In the two studies presented in this report, we sought (a) to evaluate the absolute efficacy of carteolol (i.e., vs. its vehicle) over an extended period and (b) to evaluate the utility of carteolol versus that of timolol when used concomitantly with pilocarpine. Study 1 was a double-masked, randomized, 6-week evaluation conducted in 64 patients of 1% carteolol HCl, 2% carteolol HCl, and its vehicle given twice daily in both eyes. From an unmedicated baseline intraocular pressure (IOP) of 23-25 mm Hg, mean reductions in the carteolol treatment groups ranged from 5.8 to 6.6 mm Hg (23-26% reduction). Mean reductions in heart rate were six to seven beats/min, two beats/min, and one beat/min in the 1% carteolol, 2% carteolol, and vehicle groups, respectively. Study 2 was a double-masked, randomized, 12-week evaluation of 1% carteolol HCl, 2% carteolol HCl, and 0.5% timolol in combination with pilocarpine, either 2% or 4%, in 67 patients. From an unmedicated baseline IOP of 24-29 mm Hg, mean reductions from this unmedicated baseline with combination beta-adrenoceptor antagonist/pilocarpine treatment ranged from 6 to 10 mm Hg in all groups (24-40%). Mean decreases in heart rate ranged from one to six beats/min, with no meaningful differences among the treatment groups. Based on the efficacy of twice-daily carteolol in reducing IOP by approximately 25%, as well as its efficacy when used concomitantly with pilocarpine, we suggest that clinicians may find carteolol a useful addition to their pharmacopeia in the treatment of elevated IOP.

Ocular pressure response to fluorometholone acetate and dexamethasone sodium phosphate.

The intraocular pressure elevating potentials of fluorometholone acetate ophthalmic suspension and dexamethasone sodium phosphate ophthalmic solution were compared in human subjects who were previously documented to respond to dexamethasone sodium phosphate. In this double-masked, crossover study of 17 subjects, the same eye of each subject was dosed with both steroids, instillation of the second steroid following a one-month washout period. The length of time necessary to respond with an increase of 10 mmHg was ascertained. The mean response time for fluorometholone acetate was four weeks and for dexamethasone sodium phosphate, three weeks. This difference, in favor of fluorometholone acetate, is statistically significant.

Comparative evaluation of the short-term bactericidal potential of a steroid-antibiotic combination versus steroid in the treatment of chronic bacterial blepharitis and conjunctivitis.

The effects of four days' treatment with topical Maxitrol (neomycin sulphate 3500 IU/mL, polymyxin-B sulphate 6000 IU/mL with dexamethasone 0.1%) were compared with those of Maxidex (dexamethasone 0.1% alone) in a double-masked study in 111 patients with bacterial blepharitis or conjunctivitis, 95 of whom were evaluable for efficacy. The majority of patients (N = 80) had chronic blepharitis. Maxitrol treatment resulted in a significantly greater reduction (90%) in bacterial counts and bacterial eradication (50%) compared with Maxidex (34% and 17% respectively). Maxitrol treatment also produced a significantly greater reduction in conjunctival discharge than did Maxidex, while the treatments were equally effective in alleviating other ocular signs and symptoms. It was concluded that use of a fixed dose combination steroid-antibiotic product was more effective for bacterial control and therapeutic efficacy in the treatment of chronic blepharitis and conjunctivitis patients than treatment with steroid alone. However, in the long-term treatment of chronic blepharitis the well-known toxic problems of neomycin sulphate have to be taken into account.

Renal lymphatic function following venous pressure elevation.

The renal lymphatic system plays an important role in removing excess fluid from the kidneys. Unfortunately, the factors influencing lymphatic flow are difficult to measure. We used a simple model to represent renal lymphatics as a single pressure source (PL) pushing lymph through a single resistance (RL). In anesthetized dogs, we cannulated renal lymphatics and measured lymph flow rate (QL) as we varied pressure (PO) at the outflow end of the lymphatics. There was no significant change in QL as we increased PO from -5 to 0 cm H2O. In other words, there was a plateau in the QL vs. PO relationship. At higher PO's, QL decreased linearly with increases in PO. From this linear relationship, we calculated RL as -delta PO/ delta QL and we took PL as the PO at which QL = 0 microliter/min. At baseline, RL = 0.34 +/- 0.14 (SD) cm H2O.min/microliter and PL = 8.2 +/- 4.4 cm H2O. When we increased renal venous pressure (PV) from baseline (3.5 +/- 3.0 cm H2O), the plateau in the QL vs. PO relationship extended to higher PO's, RL decreased, and PL increased. Renal interstitial fluid volume and interstitial pressure increased following elevation of PV. The extension of the QL vs. PO plateau with increasing PV suggests that renal interstitial pressure may partially collapse intrarenal collecting lymphatics which may compromise lymph flow.

Frequency and severity of osteochondrosis in horses with cervical stenotic myelopathy.

We compared the frequency and severity of osteochondrosis lesions in young Thoroughbred horses with cervical stenotic myelopathy (CSM) vs that in clinically normal Thoroughbreds of the same age. All lesions of the cervical vertebrae and appendicular skeleton were classified histologically as osteochondrosis or nonosteochondrosis and were measured for severity. Minimal sagittal diameter was significantly smaller in horses with CSM from C2 through C6; no difference was detected at C7. Severity of cervical vertebral osteochondrosis was greater in the horses with CSM, however frequency was not different. Frequency and severity of nonosteochondrosis lesions were not different in cervical vertebrae or appendicular skeleton. Frequency and severity of appendicular skeleton osteochondrosis lesions were both greater in horses with CSM. Osteochondrosis and nonosteochondrosis lesions were more severe on facets at sites of compression than on facets at noncompressed sites in horses with CSM. However, compression was also observed at sites with no articular facet lesions. The association of widespread osteochondrosis and spinal canal narrowing with CSM suggests CSM may represent a systemic failure in the development or maturation of cartilage and bone.

Surgical stapling for repair of a rectal tear in a horse.

A grade-4 rectal tear in a mare was successfully repaired per rectum, using a surgical stapling device. The mare had only minor postoperative complications. This technique has some advantages over previously described procedures, but should be reserved for use in selected cases.

Complications of nasogastric intubation in horses: nine cases (1987-1989).

Pharyngeal or esophageal trauma was diagnosed in 9 horses after nasogastric intubation. Evidence of trauma (edema or ulceration) was detected in the pharynx of 3 horses and in the esophagus of 6 horses. Complications associated with nasogastric intubation were first observed in 5 horses while they were intubated and in 4 horses after extubation. Clinical signs of pharyngeal or esophageal trauma were similar, and included salivation, bruxism, coughing, and nasal discharge. Treatment, including extubation, enteral feeding through a small nasogastric tube, or esophagostomy distal to the affected site, was attempted in 6 horses. Three of 6 treated horses survived, but 4 of 5 horses with perforated esophagus were euthanatized.