Pathophysiology of aniridia-associated keratopathy: Developmental aspects and unanswered questions.

Aniridia, a rare congenital disease, is often characterized by a progressive, pronounced limbal insufficiency and ocular surface pathology termed aniridia-associated keratopathy (AAK). Due to the characteristics of AAK and its bilateral nature, clinical management is challenging and complicated by the multiple coexisting ocular and systemic morbidities in aniridia. Although it is primarily assumed that AAK originates from a congenital limbal stem cell deficiency, in recent years AAK and its pathogenesis has been questioned in the light of new evidence and a refined understanding of ocular development and the biology of limbal stem cells (LSCs) and their niche. Here, by consolidating and comparing the latest clinical and preclinical evidence, we discuss key unanswered questions regarding ocular developmental aspects crucial to AAK. We also highlight hypotheses on the potential role of LSCs and the ocular surface microenvironment in AAK. The insights thus gained lead to a greater appreciation for the role of developmental and cellular processes in the emergence of AAK. They also highlight areas for future research to enable a deeper understanding of aniridia, and thereby the potential to develop new treatments for this rare but blinding ocular surface disease.

An attempt to optimize the outcome of penetrating keratoplasty in congenital aniridia-associated keratopathy (AAK).

PURPOSE: To propose an optimized microsurgical and medical approach to reduce the risk of complications after penetrating keratoplasty (PKP) in patients with aniridia-associated keratopathy (AAK). METHODS: Retrospective observational case series of 25 PKP performed in 16 patients with AAK. Preoperative indications were endothelial decompensation and vascularized scars (68%) or graft failure (32%) due to limbal stem cell deficiency. The optimized approach included a combination of a small corneal graft size (around 7.0 mm), interrupted 10-0nylon sutures, simultaneous AMT as a patch, large bandage contact lens, temporary lateral tarsorrhaphy, postoperative autologous serum eye drops, and systemic immunosuppression. Main outcome measures included: visual acuity, transplant survival, and complications encountered during follow-up of 107 weeks on average. RESULTS: A complete modified keratoplasty scheme was used in 10 of 25 PKP (group 1), while at least one of the modifications was missing in the other 15 PKP (group 2). After 8 weeks of follow-up, the epithelium was closed in 23 eyes. Visual acuity improved in 19 eyes at 6 months of follow-up, and remained stable in six eyes. None of the eyes showed a decrease in visual acuity. At the last post-operative follow-up, this visual improvement persisted in 14 eyes and graft survival rate after 156 weeks (3 years) was 69% in group 1 versus 44% in group 2 (p = 0.39, log-rank test). Secondary corneal neovascularization (8%), scarring (4%), ulcer (4%), or graft rejection (8%) happened mostly in the second group which was missing at least one of the suggested modifications. CONCLUSIONS: PKP in congenital aniridia must be considered as a high-risk keratoplasty. An optimized therapeutic approach seems to be promising in order to reduce the postoperative complication rate in these most difficult eyes.

Abnormal neovascular and proliferative conjunctival phenotype in limbal stem cell deficiency is associated with altered microRNA and gene expression modulated by PAX6 mutational status in congenital aniridia.

PURPOSE: To evaluate conjunctival cell microRNA (miRNAs) and mRNA expression in relation to observed phenotype of progressive limbal stem cell deficiency in a cohort of subjects with congenital aniridia with known genetic status. METHODS: Using impression cytology, bulbar conjunctival cells were sampled from 20 subjects with congenital aniridia and 20 age and sex-matched healthy control subjects. RNA was extracted and miRNA and mRNA analyses were performed using microarrays. Results were related to severity of keratopathy and genetic cause of aniridia. RESULTS: Of 2549 miRNAs, 21 were differentially expressed in aniridia relative to controls (fold change ≤ -1.5 or ≥ +1.5). Among these miR-204-5p, an inhibitor of corneal neovascularization, was downregulated 26.8-fold in severely vascularized corneas. At the mRNA level, 539 transcripts were differentially expressed (fold change ≤ -2 or ≥ +2), among these FOSB and FOS were upregulated 17.5 and 9.7-fold respectively, and JUN by 2.9-fold, all being components of the AP-1 transcription factor complex. Pathway analysis revealed enrichment of PI3K-Akt, MAPK, and Ras signaling pathways in aniridia. For several miRNAs and transcripts regulating retinoic acid metabolism, expression levels correlated with keratopathy severity and genetic status. CONCLUSION: Strong dysregulation of key factors at the miRNA and mRNA level suggests that the conjunctiva in aniridia is abnormally maintained in a pro-angiogenic and proliferative state, and these changes are expressed in a PAX6 mutation-dependent manner. Additionally, retinoic acid metabolism is disrupted in severe, but not mild forms of the limbal stem cell deficiency in aniridia.

Colles' fractures: functional treatment in supination.

PURPOSE OF THE STUDY: Abraham Colles classified and described fractures of the distal epiphyseal radius. He recommended the arm should be immobilized in a cast that extends from the base of the fingers to above the elbow, while holding this joint at ninety degrees of flexion the forearm in pronation and the wrist in slight flexion and ulnar deviation. We identified the brachioradialis muscle as the main culprit in the frequently observed loss of reduction of the fracture. Since the brachioradialis is attached to the distal region of the radius and functions as a flexor of the elbow when the forearm is in pronation, its stimulation easily displaces a reduced fracture, particularly if its geometry suggests axial instability. We concluded that post-reduction stabilization in supination was more desirable than in pronation. MATERIAL AND METHODS: Prospective study of one hundred and fifty-six patients suffering from Colles' fractures who were treated with the functional method. Approximately one-half of the fractures were immobilized in pronation and the other half in supination. The median age of the patients was 49 years. After approximately eleven days of immobilization in an above-the-elbow cast that held the forearm in a relaxed attitude of supination and the wrist in slight flexion and ulnar deviation, a new cast or brace was applied. The appliance permitted flexion of the elbow and slightly limited extension. We utilized modified Lindstom criteria to assess radiological results, according to types of fractures and by groups treated in supination and pronation. RESULTS: In the type I and III (non-displaced) fracture series there appeared to be no significant difference in the functional results between the pronation and supination treated groups. In the type II category, in the supinated fractures, there were 9 excellent, 4 good and no fair or poor results. In the pronated group 9 excellent, 8 good and one fair result. The functional results in type IV fractures treated in supination were excellent in 11 instances, good in 7 and fair in 2. In fractures treated in pronation there were 5 excellent, 10 good and 5 fair results. There were no poor results in either group. 85% of type II fractures and 85% of type IV fractures treated in supination had excellent or good results. In the pronation group, 67% had excellent or good results in type II and 40% in type IV classification. In combining the results for all types of braced Colles' fractures, (I-IV) 93% of the supination group and 87% of the pronation group achieved excellent or good functional results. In analyzing overall results regardless of type of fracture or position of immobilization, 90% of the patients had excellent or good results. CONCLUSION: We treated Colles' fractures in supination and compared the results with those obtained when treated in pronation. The results indicated a lower incidence of re-displacement in the supination group. We developed a forearm brace that permits flexion of the elbow, but prevented pronation of the forearm, and limited extension of the elbow in approximately the last fifteen degrees. It permits minimally limited flexion of the wrist but prevents wrist dorsiflexion. It makes impossible any radial deviation. The place of surgery in the management of Colles' fractures should be limited to those fractures that when treated by non-surgical means are not likely to render satisfactory functional and cosmetic results. There is not at this time a consensus as to when to use the surgical approach. The complication rate from the surgery have not clearly identify superiority of one over the other. Nonetheless, the surgical treatment has a definite place in the armamentarium of the orthopaedic surgeon. In a number of situations, it is the treatment of choice.

Enhancing clinical skill development through an Ambulatory Medicine Teaching Programme: an evaluation study.

BACKGROUND: Teaching of clinical skills traditionally takes place in hospital wards and outpatient settings. However high acuity and short hospital stays means there are fewer suitable inpatients available for teaching; and time pressures limit students' involvement in other settings. The Ambulatory Medicine Programme was established to develop undergraduate medical students' clinical skills by providing increased exposure to patients with a wide range of chronic medical conditions, in a dedicated learning environment. METHOD: A mixed qualitative/quantitative approach was used to evaluate the Programme. This research focuses on staff and student perspectives of teaching and learning in Ambulatory Medicine compared with inpatient and outpatient settings; identifies which teaching methods are considered most effective; and determines the transferability of learning. Patients' perspectives of being involved in student teaching are also reported. RESULTS: Results show that the programme has made a positive impact on students' development of clinical skills, which are transferable to the clinical setting. Patients enjoy being involved and find it personally satisfying. CONCLUSIONS: The Ambulatory Medicine Programme is an effective way of developing medical students' clinical skills by providing focussed teaching with real patients in a dedicated learning environment.

The effect of spontaneous mutations on competitive ability.

Understanding the impact of spontaneous mutations on fitness has many theoretical and practical applications in biology. Although mutational effects on individual morphological or life-history characters have been measured in several classic genetic model systems, there are few estimates of the rate of decline due to mutation for complex fitness traits. Here, we estimate the effects of mutation on competitive ability, an important complex fitness trait, in a model system for ecological and evolutionary genomics, Daphnia. Competition assays were performed to compare fitness between mutation-accumulation (MA) lines and control lines from eight different genotypes from two populations of Daphnia pulicaria after 30 and 65 generations of mutation accumulation. Our results show a fitness decline among MA lines relative to controls as expected, but highlight the influence of genomic background on this effect. In addition, in some assays, MA lines outperform controls providing insight into the frequency of beneficial mutations.

A surgical technique for the prevention of femoral lysis in cement total hip arthroplasty.

Femoral bone lysis in total hip arthroplasty is thought to be primarily due to polyethylene or metal debris arising from the femoral or acetabular components. The debris appears to gradually seep into the cement/ bone interface, eventually generating the chemical reaction that produces lysis.We experimented with a surgical technique that attempts to construct a proximal bony barrier preventing migration of debris. Following the injection of the acrylic cement and the insertion of the femoral component, but prior to complete polymerization of the cement, bone chips are pressed over the cement, in contact with the viable femoral cortex. The bone chips become rigidly fixed; probably regain viability from the femoral cortex, and seal the proximal femur. In this manner, debris cannot travel into the femoral canal. Although we do not have anatomical evidence that a viable bony seal has formed the absence of lysis and bone/cement radiolucent lines over a period of time ranging from three to fourteen years suggests the permanent presence of a physiological barrier. Attempts to identify the permanency of the bony seal by means of CT scans proved inconclusive. Key words: total hips, lysis, femoral lysis, cortical graft.

Functional treatment of closed segmental fractures of the tibia.

PURPOSE OF THE STUDY Segmental tibial fractures are commonly believed to be more difficult to manage, requiring surgical treatment. Our experience with forty-eight segmental tibial fractures suggests that these fractures, if closed and with shortening of an acceptable initial degree and a corrected deformity, may be successfully treated with functional braces. MATERIAL AND METHODS Forty-eight closed segmental fractures of the tibia that had initial shortening .12 mm and angular deformity manually corrected to .7 degrees were stabilized in an above-the-knee cast for a median time of 33 days and a mode of 15 days. They were subsequently stabilized in a functional brace that allowed unencumbered motion of all joints. All other segmental fractures outside the established parameters were managed by other methods. RESULTS All fractures healed at a median time of 15.3 weeks. The final shortening was 4.7 millimeters with a mode of 12 millimeters. The maximum shortening was 14 millimeters. Fractures healed with a medial-lateral (M.L) angular deformities ranging zero to 19 degrees, a median of 5.9 degrees and a mode of 3.4 degrees. CONCLUSION The relatively early introduction of weight bearing and the freedom of motion of all joints that the brace permits seem to result in motion at the fracture site, which in turn enhances osteogenesis. As we have previously documented, the initial shortening that closed tibial fractures experience does not increase with the physiological use of the extremity. The final shortening and angulation observed in most of the fractures should not be considered complications, simply inconsequential deviations from the normal. The same should apply to closed segmental fractures.

[Humeral diaphyseal fractures: functional bracing]. / Funktionelle Behandlung bei Humerusschaftfrakturen.

Functional bracing of humeral diaphyseal fractures was conceived after initial experiences with a similar method was used in the management of diaphyseal tibial fractures. Over the years, tibial functional bracing underwent major evolutionary changes, and found its indications basically limited to a smaller group of fractures, consisting of closed, axially unstable fractures that experience at the time of the injury an acceptable degree of shortening, and to transverse fracture that are appropriately reduced and rendered stable. On the other hand, functional bracing of diaphyseal humeral fractures has, maintained the initial indications, contraindications and methodology. This article describes the concept, indications and contraindications of functional bracing of humeral diaphyseal fractures and provides results of 620 fractures with complete follow-up. In 97.5% of the patients, the average healing time was 11.5 weeks. 16 patients (2.5%) required operative intervention because of a nonunion and 4 patients (<1 degrees) of the patient had a refracture after brace removal. Nerve function did not return in only one of the 67 patient who had radial nerve palsy.

A radiographic review of 135 total hip Charnley arthroplasties followed between 15 and 35 years.

The long-term radiologically interpreted results of low-friction Charnley hip arthroplasties have been previously suggested to be influenced by surgical details, such as orientation of the femoral component, degree of coverage of the plastic acetabulum and other features. We carefully analyzed the radiographs of 135 Charnley arthroplasties that had remained functional, had not been revised and had follow-ups between 15 and 35 years. Several common denominators were identified amongst these radiographs: 93.5% arthroplasties had 100% coverage of the acetabular component; 88% had acetabular inclination between 40-45 degrees ; 84.5% had a proximal/medial column of cement between 3 and 5 millimeters at the level of femoral head resection; 81% had a femoral canal/stem ratio more than 50%; and 84% had a column of cement that extended below the tip of the prosthesis. This study supports the importance of technical surgical details that enhance the chances of long-term survival of cemented total hip arthroplasties.

[Mobility of unstable fractures of the odontoid during helmet removal. A biomechanical study]. / Verhalten der instabilen Densfraktur bei Abnahme des Motorradhelms. Eine biomechanische Untersuchung.

In severe motorcyclist accidents unstable injuries of the cervical spine can usually not be excluded before an X-ray has been taken in the hospital. Despite this the helmet has to be taken off at the place of the accident in order to provide adequate treatment and airway management of the injured driver. There are no data in the current literature showing what happens to unstable lesions of the cervical spine during helmet removal. An experimental unstable lesion of the cervical spine was created by an osteotomy of the odontoid in 10 fresh frozen cadavers with intact soft tissues. All motions occurring in the segments C1-2 and C2-3 during helmet removal were recorded by fluoroscopy. The average motion in the unstable segment C1-2 was 23.7 degrees during a full range of extension-flexion movement of the cervical spine without any signs of dislocation of the segment. After application of the helmet there was one case of dislocation of C1-2 in neutral supine position already, and two further cases of dislocations during helmet removal. The average motion of C1-2 recorded during helmet removal was 19.0 degrees (2-25 degrees ), median 18.0 degrees. In order to avoid fracture dislocations and motion in the unstable upper cervical spine the helmet should better be cut in pieces at the place of the accident. There is a need for discussions with helmet producers to develop a new generation of helmets that can be removed easily without manipulating the head.

Patterns of genetic architecture for life-history traits and molecular markers in a subdivided species.

Understanding the utility and limitations of molecular markers for predicting the evolutionary potential of natural populations is important for both evolutionary and conservation genetics. To address this issue, the distribution of genetic variation for quantitative traits and molecular markers is estimated within and among 14 permanent lake populations of Daphnia pulicaria representing two regional groups from Oregon. Estimates of population subdivision for molecular and quantitative traits are concordant, with QST generally exceeding GST. There is no evidence that microsatellites loci are less informative about subdivision for quantitative traits than are allozyme loci. Character-specific comparison of QST and GST support divergent selection pressures among populations for the majority of life-history traits in both coast and mountain regions. The level of within-population variation for molecular markers is uninformative as to the genetic variation maintained for quantitative traits. In D. pulicaria, regional differences in the frequency of sex may contribute to variation in the maintenance of expressed within-population quantitative-genetic variation without substantially impacting diversity at the genic level. These data are compared to an identical dataset for 17 populations of the temporary-pond species, D. pulex.

A new modular testing system for biomechanical evaluation of tibial intramedullary fixation devices.

This biomechanical study was performed to evaluate a new modular, tibial testing system developed for analysis of tibial nails and their locking screws.A new testing system, consisting of five modules, was designed to simulate a tibia. For this study one module was removed to simulate a 55-mm distal tibial defect inducing maximum loading on the distal portion of the implant and locking bolts. The tibial load offsets were 23 mm proximally and 10 mm distally medial to the centreline of the tibial shaft to simulate the location of the expected resultant load during the peak loading and inversion torque on the ankle during the gait cycle. Four solid tibial nails (STN, Stryker-Howmedica-Osteonics, Kiel, Germany) were tested to static failure and 15 nails were tested dynamically. Our results showed that the solid tibial nails fractured in the testing device in the same manner and location as they do in clinical series. Evaluation of the results showed the mean fatigue limit of the STN to be 1.4 kN for 500,000 cycles with a standard deviation (S.D.) of 0.33 kN. This biomechanical study establishes a standard technique for the biomechanical testing of tibial nails, in a clinically relevant manner, avoiding the inconsistency of cadaver bone tests. As it is a standardised test set-up this new modular testing system could serve as a standard by which small diameter tibial nails and other devices could be evaluated and compared with other systems currently in use.

Triangulated pedicle screw construct technique and pull-out strength of conical and cylindrical screws.

To compare the mechanical effectiveness of a new conical screw design with a conventional cylindrical screw design, the screw insertion time, torque, and pull-out strength of single-pedicle screw and triangulated-pedicle screw constructs of each type of screw were compared in human cadaveric vertebral bodies. The time required to insert the conical screws was less than that required for cylindrical screws. Regression analysis revealed a positive correlation between insertion torque and pull-out strength of single and triangulated constructs of each type of screw. The conical screw had a greater increase than the cylindrical screw in the pull-out strength of triangulated pedicle screw constructs. Application of the new conical screw design was significantly faster, and the new screw had better mechanical fixation to the vertebral body than did the conventional cylindrical screw tested.

The stabilizing effects of different orthoses in the intact and unstable upper cervical spine: a cadaver study.

BACKGROUND: Although cervical orthoses are frequently used in prehospital stabilization and in the definitive treatment for lesions of the cervical spine, there is little information about the control of extension-flexion, lateral bending, and rotation given to individual segments by different designs. METHODS: In an experimental in vitro study with four fresh frozen cadavers, the halo vest was compared with the soft collar, prefabricated Minerva brace, and Miami J collar. The controlling effects for the segments C1-2 and C2-3 were tested for all four devices in the intact and the unstable spine with an Anderson type II fracture of the odontoid. RESULTS: All four orthoses reduced the range of motion at both C1-2 and C2-3 of the intact spine significantly, although none of the three semirigid devices provided a halo-like immobilization in the intact spine. The osteotomy of the odontoid increased the range of motion in the segment C1-2. The soft collar did not give any clinically relevant stability to the unstable spine. Miami J and Minerva brace provided a similar moderate control in the sagittal plane but a much better control of "torque" in the upper cervical spine. The halo vest did not allow any measurable motion in any plane with our experimental external loading. CONCLUSION: The halo vest seems to be the first choice for conservative treatment of unstable injuries of the upper cervical spine, although pin track problems, accurate fitting of the vest, and a lack of patient compliance lead to clinical failures.

Functional bracing for the treatment of fractures of the humeral diaphysis.

BACKGROUND: Nonoperatively treated fractures of the humeral diaphysis have a high rate of union with good functional results. However, there are clinical situations in which operative treatment is more appropriate, and, though interest in plate osteosynthesis has decreased, intramedullary nailing has gained popularity in recent years. We report the results of treating fractures of the humeral diaphysis with a prefabricated brace that permits full motion of all joints and progressive use of the injured extremity. METHODS: Between 1978 and 1990, 922 patients who had a fracture of the humeral diaphysis were treated with a prefabricated brace that permitted motion of adjacent joints. The injured extremities were initially stabilized in an above-the-elbow cast or a coaptation splint for an average of nine days (range, zero to thirty-five days) prior to the application of the prefabricated brace. Orthopaedic residents, supervised by teaching staff, provided follow-up care in a special outpatient clinic. Radiographs were made at each follow-up visit until the fracture healed. RESULTS: We were able to follow 620 (67 percent) of the 922 patients. Four hundred and sixty-five (75 percent) of the fractures were closed, and 155 (25 percent) were open. Nine patients (6 percent) who had an open fracture and seven (less than 2 percent) who had a closed fracture had a nonunion after bracing. In 87 percent of the 565 patients for whom anteroposterior radiographs were available, the fracture healed in less than 16 degrees of varus angulation, and in 81 percent of the 546 for whom lateral radiographs were available, it healed in less than 16 degrees of anterior angulation. At the time of brace removal, 98 percent of the patients had limitation of shoulder motion of 25 degrees or less. We were unable to follow most of the patients long-term, as they did not return to the clinic once the fracture had united and use of the brace had been discontinued. CONCLUSIONS: Functional bracing for the treatment of fractures of the humeral diaphysis is associated with a high rate of union, particularly when used for closed fractures. The residual angular deformities are usually functionally and aesthetically acceptable. The present study illustrates the difficulties encountered in carrying out long-term follow-up of indigent patients treated in charity hospitals that are affiliated with teaching institutions. These difficulties are also becoming common with patients insured under managed-care organizations and are frequent in our peripatetic population.

Functional fracture bracing.

Functional bracing is an effective therapeutic modality in the management of selected fractures of the tibia, humerus, and ulna, particularly low-energy injuries. In the case of tibial fractures, it is applicable only to reduced transverse fractures and to axially unstable fractures with an acceptable degree of shortening. The rate of union of tibial fractures after functional bracing is approximately 97%. The initial shortening noted with closed tibial fractures rarely increases with weight bearing. Shortening has been reported to be as little as 12 mm in 95% of patients, with angulation of 8 degrees in 90%. Such minimal shortening and angulation do not affect functional results. In closed and type I open diaphyseal humeral fractures treated with functional braces, the nonunion rate is approximately 3%. Most of the reported residual angular deformities have been functionally and cosmetically acceptable. For isolated ulnar fractures, the nonunion rate is approximately 2%. Functional fracture bracing is predicated on the premise that motion at the fracture site encourages osteogenesis. The method is applicable only to selected fractures, and it is necessary to have a clear understanding of its rationale, indications, and technique.