Incidence of ocular side effects with intravenous zoledronate: secondary analysis of a randomized controlled trial.

SUMMARY: This prospective study showed that the incidence of acute anterior uveitis, confirmed by ophthalmic examination, in patients receiving intravenous zoledronate infusions as part of a randomized controlled trial for fracture prevention is 1.1%. INTRODUCTION: We prospectively investigated the incidence of ocular side effects after a single intravenous zoledronate infusion. METHODS: In a secondary analysis of a double-blind, placebo-controlled trial in which early post-menopausal women (N=1054) with normal bone density or osteopenia were randomized to infusion of zoledronate 5 mg (N=703) or placebo (N=351), we analyzed significant adverse ocular events occurring within 3 months. RESULTS: Fourteen participants reported ocular symptoms after the infusion. All were examined by an ophthalmologist and eight were diagnosed with acute anterior uveitis (AAU) and one with sectoral episcleritis. The incidence of AAU and episcleritis was 1.1% (95% CI 0.5-2.1) and 0.1% (95% CI 0.0-0.7), respectively, in the zoledronate group and 0% for both conditions in the placebo group (95% CI 0.0-0.8). The mean time from infusion to symptom onset for AAU was 3 days (range 2-4). Three cases were bilateral. AAU was mild-moderate in seven participants and severe in one. All affected eyes were treated with topical cyclopentolate 1% (to break, or minimize, posterior synechiae), and intensive, potent, topical corticosteroids with a tapering regime based on treatment response. The mean duration of topical corticosteroid was 26±10 days (range 17-44). The mean, best corrected visual acuity was 20/20 (range 20/20-20/40) at presentation, which remained unchanged after AAU resolution. None of the participants lost vision, and no long-term sequelae were reported at last follow-up (range 3-13 months post-infusion). CONCLUSIONS: Prescribers should inform patients about the possibility of ocular side effects with zoledronate infusions and refer promptly to an ophthalmologist if symptoms develop.

Effect of early skin-to-skin contact following normal delivery on incidence of hypothermia in neonates more than 1800 g: randomized control trial.

OBJECTIVE: To investigate the impact of early skin-to-skin contact (SSC) provided for first 24 h on incidence of hypothermia in stable newborns weighing 1800 g or more during first 48 h of life. STUDY DESIGN: Stable newborns (term and late preterm: Mean gestational age 37.7 (1.35) weeks, range 34-40 weeks) having birth weight 1800 g or more (Mean weight 2605.6 (419.8) grams) were enrolled after approval from Institutional Human Research Ethics Committee (CTRI/2013/06/003790) and randomized into early SSC (intervention group) and conventional care (control group). Initial care in the delivery room for few minutes immediately after birth in both the groups was given under radiant warmer. In the intervention group, newborns were provided SSC by their mother started between 30 min and 1 h after birth for first 24 h with minimal interruption and were provided conventional care other than SSC for next 24 h of life. In the control group, newborns were kept with their mother and received conventional care other than SSC for first 48 h. Temperature and heart rate of newborns were recorded at 30 min, 1, 2, 3, 4, 5, 6, 12, 24 and at 48 h of life in both the groups. Independent Samples t-Test and relative risk were used to analyze the data. RESULT: Both groups had 50 neonates each with similar baseline characteristics. Heart rates were in normal range in both the groups. The intervention group provided an average (s.d.) of 16.98 (0.28) h of SSC over the first 24 h period. The mean temperature was significantly high in the SSC group at all time intervals starting from 1 to 48 h (P<0.05 for all). In the SSC group only two newborns (4%) had mild hypothermia (cold stress), and, of these two newborns, one had two episodes of hypothermia. All these three episodes of hypothermia occurred within first 3 h of life. In the control group 16 newborns (32%) developed hypothermia (temperature<36.5 °C) during first 48 h of life. Of them, 11 newborns had single episode, 4 newborns had two episodes and one newborn had three episodes of hypothermia. Of these 22 hypothermic episodes, 20 occurred in the first 6 h of life and 2 episodes occurred at 48 h of life. Moderate hypothermia was seen in two newborns, whereas rest had mild hypothermia. The relative risk of developing hypothermia in the control group as compared with the SSC group was 8.00 (95% CI 1.94-32.99). There was no seasonal variation in incidence of hypothermia in both the groups. CONCLUSION: Newborns in the SSC group achieved rapid thermal control as compared with the control group. Early SSC for 24 h after birth decreases incidence of hypothermia for initial 48 h of life. Early SSC needs to be aggressively promoted in term and late-preterm newborns to reduce incidence of hypothermia.

Investigation of erectile dysfunction.

Erectile dysfunction (ED) represents a common and debilitating condition with a wide range of organic and non-organic causes. Physical aetiologies can be divided into disorders affecting arterial inflow, the venous occlusion mechanism or the penile structure itself. Various imaging modalities can be utilised to investigate the physical causes of ED, but penile Doppler sonography (PDS) is the most informative technique, indicated in those patients with ED who do not respond to oral pharmacological agents (e.g. phosphodiesterase type 5 inhibitors). This review will examine the anatomical and physiological basis of penile erection, the method for performing PDS and features of specific causes of ED, and will also consider the alternative imaging modalities available.

Priapism: pathophysiology and the role of the radiologist.

Priapism is defined as a penile erection that persists for 4 h or longer and is unrelated to sexual activity. Its identification is important as lack of timely treatment (particularly of the low flow/ischaemic subgroup) can result in persisting erectile dysfunction as a consequence of irreversible corporal fibrosis. This review describes the physiology and anatomy of the normal erection, the aetiology and pathophysiology of the different types of priapism, and the role of the radiologist in the management of the condition. The treatment of iatrogenic priapism following intracavernosal injection of pharmacostimulant is discussed.

Transvenous embosurgery of a left sigmoid sinus dural arteriovenous fistula via a retrograde approach from the superior ophthalmic vein, cavernous and inferior petrosal sinuses.

The efficacy and safety of transvenous embosurgery for sigmoid sinus dural arteriovenous fistula (DAVF) using the internal jugular vein approach is well known. Embosurgery of cavernous sinus DAVF has also been described utilizing a superior ophthalmic vein approach. The first report of a sigmoid sinus DAVF endosurgical repair via a superior ophthalmic vein approach in a patient without internal jugular vein access is presented.

Targeting CYP450 modulation to decrease the risk of induced cataract in the experimental model.

BACKGROUND: Diabetes is one of the major causes of cataract. Some drugs prescribed for the treatment of diabetes are the modulators of CYP450, which may alter the risk of cataract. OBJECTIVE: To study the effect of CYP450 modulation in galactosemic cataract. MATERIALS AND METHODS: Male Sprague-Dawley suckling rats were allotted to four groups (n = 6), as follows: Group 1: Normal control, Group 2: Galactose control, Group 3: CYP450 inhibitor pretreated and Group 4: CYP450 inducer pretreated. Cataract was induced in animals of all groups except group 1 by feeding them galactose (50%), 21 days after parturition. From the eighteenth day of life, CYP450 inhibitor (nifedipine; 8.1 mg/kg) and CYP450 inducer (pioglitazone; 3.8 mg/kg) were given orally to groups 3 and 4, respectively. The maturation pattern of the cataract was observed by an operating microscope, every third day. Biochemical changes in the lenses of all groups, for example, CYP450 activity expressed as ΅M NADPH oxidized / unit time, alterations in the levels of total proteins, soluble proteins, and reduced glutathione (GSH) following the induction of cataract, were estimated. RESULTS: The microscopic examination of the lenses indicated that CYP450 inhibitor pre-treatment delayed (fourteenth day) the occurrence of cataract, while CYP450 inducer pretreatment demonstrated an early (ninth day) cataract as compared to galactose control rats (twelfth day). A significant decrease and increase in CYP450 activity was observed with the CYP450 inhibitor and inducer pre-treatment, respectively. There was no alteration in the GSH level, but a significant increase in total and soluble protein was found in groups 3 and 4 as compared to group 2. CONCLUSION: CYP450 may have a role in the initiation of cataract without any effect on the maturation pattern, as revealed by the delayed occurrence of cataract with the CYP450 inhibitor and an early onset of cataract with the CYP450 inducer.

Corticosteroid-induced intraocular pressure elevation in keratoconus is common following uncomplicated penetrating keratoplasty.

AIMS: To determine the incidence of postkeratoplasty intraocular pressure (IOP) elevation in the eyes of subjects with keratoconus and establish the relationship between IOP and corticosteroid administrations in this population. METHODS: Following strict inclusion/exclusion criteria, a retrospective analysis was performed on a consecutive series of penetrating keratoplasties performed for keratoconus observing a standardised surgical and postoperative regimen in Auckland, New Zealand. Patient demographics, ocular, medical, and family history, and pre- and postoperative data were recorded until 12 months postkeratoplasty. RESULTS: In all, 57 eyes of 48 patients were included-31% New Zealand Europeans, 42% Pacific people, 15% Maori, and 12% other. Eighteen eyes (32%) of 17 patients (35%) exhibited elevated IOP and 12 (21%) eyes exhibited moderate-to-severe elevation of IOP. IOP elevation occurred 3-6 months postkeratoplasty in 78% of eyes. Elevated IOP was significantly less common in Maori and Pacific peoples (P=0.02). All eyes except one required reduction/cessation of corticosteroids to normalise IOP. CONCLUSIONS: The incidence of presumed steroid-related postkeratoplasty IOP elevation, in 35% of subjects with keratoconus, is markedly higher in this New Zealand study than previously reported in the US and UK studies. Further clinical and genetic analysis of associations between keratoconus and steroid-induced IOP elevation and glaucoma might improve our current understanding of this condition.

Laser-scanning in vivo confocal microscopy reveals two morphologically distinct populations of stromal nerves in normal human corneas.

BACKGROUND: The purpose of this study was to use laser scanning in vivo confocal microscopy to elucidate the location and morphology of stromal nerves in the normal human central cornea. METHODS: Analysis was performed via an established database of laser-scanning in vivo confocal microscopy on images of the central cornea of normal subjects. The depth and morphology of the stromal nerves were determined. RESULTS: The population of this study consisted of 99 eyes of 99 healthy subjects (38 male, 61 female). The mean age of the group was 34.7 (SD 13.3, range 13-84) years. Two morphologically different populations of stromal nerves were observed: (1) straight, dichotomous branching nerves; and (2) tortuous nerves with a beaded appearance. The mean recorded depth of straight stromal nerves (186 (SD 66) mum) was significantly deeper than the mean depth of the tortuous stromal nerves (140 (SD 87) mum) (p<0.001). CONCLUSIONS: The current study identified two morphologically distinct stromal nerve populations in the normal human cornea. We hypothesise that the two morphological nerve populations described here may represent functionally heterogeneous nerves. Further research is required to determine if these in fact represent different types of sensory nerves.

In vivo confocal microscopy of human corneal nerves in health, in ocular and systemic disease, and following corneal surgery: a review.

The exponential evolution of in vivo confocal microscopy (IVCM) has led to a significant enhancement in our knowledge of the living cornea in both its physiological and pathological states. Studies using white light and coherent light-based IVCM have enabled detailed quantitative analysis of sub-basal nerve parameters, and have also resulted in the elucidation of the two-dimensional architecture of the normal corneal sub-basal nerve plexus. However, accurate and repeatable methods for quantitative analysis of stromal nerves imaged by IVCM remain to be developed. The effect of corneal surgery on central corneal nerves has been well documented in many IVCM studies, and these studies provide an indication of the regenerative capacity of corneal nerves. IVCM has also clearly demonstrated the involvement of corneal nerves in diseases such as keratoconus, although it remains unclear whether these alterations are a cause of, or occur secondary to, the disease process. IVCM has also been proposed as non-invasive method of accurately diagnosing and assessing the progression of diabetic neuropathy, highlighting the potential application of this technique as an indicator of systemic disease. This review consolidates our knowledge of how IVCM has contributed significantly to our greater understanding of corneal nerves in the living human cornea in health and disease.

Identifying relationships between tomography-derived corneal thickness, curvature, and diameter and in vivo confocal microscopic assessment of the endothelium in healthy corneas of young adults.

PURPOSE: Despite the importance of a healthy endothelial layer in anterior segment surgery, the possible influence of corneal parameters on endothelial cell density (ECD) has largely been ignored in the young adult eye. This study investigated the possible associations between corneal tomographic parameters and ECD values in young adults. METHODS: Subjects aged 21-30 years, with normal corneas were recruited. Mean ECD, mean cell area (MCA), coefficient of variation for cell area (COVA), and proportion of hexagonal cells were derived by in vivo confocal microscopy. The Orbscan II system was used to measure corneal parameters including: thickness, horizontal corneal diameter, corneal curvature, anterior and posterior elevation, and eccentricity. RESULTS: Sixty-two subjects (42 female, 20 male) were included (mean age 25+/-3 years). Overall mean ECD was 3169+/-309 cells/mm(2) with no differences between genders. Mean percentage of hexagonality was 53+/-5%, male subjects (55%) had a higher percentage of hexagonal cells than female subjects (51%) (P=0.02). Central corneal thickness (CCT) was 529+/-43 microm. Central ECD was significantly correlated with CCT (Pearson's r=0.26, P=0.04). However, horizontal corneal diameter (r=0.19, P=0.14), anterior corneal curvature (r=-0.07, P=0.6), and posterior corneal curvature (r=-0.07, P=0.6) were not correlated with ECD or percentage of hexagonality. There was no statistically significant association between anterior chamber depth (3.6+/-0.3 mm) and ECD (r=0.15, P=0.3). CONCLUSION: Corneal thickness is related to ECD in normal young adult eye, with lower ECD values identified in thinner corneas; however, corneal diameter and corneal curvature do not have a significant correlation with ECD.

Laser scanning in vivo confocal microscopy and quantitative aesthesiometry reveal decreased corneal innervation and sensation in keratoconus.

PURPOSE: The purpose of this study was to quantitatively analyse laser scanning in vivo confocal microscopy images of the corneal epithelium and sub-basal nerve plexus in patients with keratoconus and to correlate these microstructural observations with corneal sensitivity. METHODS: A total of 31 eyes of 31 normal human subjects, and 27 eyes of 27 subjects with an established diagnosis of keratoconus were recruited. Twelve subjects with keratoconus had never worn contact lenses (K-NCL). Fifteen subjects with keratoconus wore contact lenses routinely (K-CL). All eyes were examined using slit-lamp biomicroscopy, Orbscan topography, non-contact corneal aesthesiometry, and laser scanning in vivo confocal microscopy. RESULTS: Central corneal sensation was significantly lower in K-CL compared to normal (P=0.028). However, there was no significant difference in corneal sensation between the normal and K-NCL groups (P=0.059). Both sub-basal nerve density (P<0.001) and basal epithelial density (P<0.001) were significantly lower than normal in all keratoconic subjects. Central corneal sensation was only significantly correlated with sub-basal nerve density (P=0.001) and was not significantly correlated with any of the basal epithelial parameters. Sub-basal nerve density showed significant positive correlation with basal epithelial density (P<0.001). CONCLUSION: This quantitative study reveals decreased corneal innervation, sensation, and basal epithelial density in keratoconus. The results of this study provide strong evidence that both the sub-basal nerves and the basal epithelium may be involved in the pathogenesis of keratoconus, although it is uncertain whether these are primary or secondary changes.

The penetration of RealSeal primer and Tubliseal into root canal dentinal tubules: a confocal microscopic study.

AIM: To compare penetration depth into dentinal tubules of RealSeal with that of a well-established endodontic sealer (Tubliseal) by means of confocal microscopy. METHODOLOGY: Twenty sound extracted, single-rooted premolars were selected. Following completion of root canal instrumentation, the teeth were divided into two groups using a stratified sampling method, ranking teeth according to size. In group 1, 10 teeth were filled with Gutta-percha and Tubliseal using cold lateral condensation. In group 2, 10 teeth were filled with RealSeal. Both sealers were labelled with Rhodamine B dye. The teeth were sectioned parallel to their long axis resulting in 20 specimens per group. Confocal microscopy was used to assess the penetration depths of the sealers at three sites for each specimen (coronal, middle and apical). Data were analysed statistically using Stata Release 9.1. RESULTS: The penetration depth of RealSeal in each one of the thirds of the root canal was found to be higher than that of Tubliseal (P < 0.05). The penetration depths of the two sealers was found to be significantly different (P = 0.001). The mean penetration value for the RealSeal group was 908.8 microm whereas the mean value for the Tubliseal group was 139.5 microm. CONCLUSIONS: The penetration depth of RealSeal into the root dentinal tubules is significantly greater than that of Tubliseal.

Type 1 Stickler syndrome: a histological and ultrastructural study of an untreated globe.

AIMS: To present a histological and ultrastructural study of an untreated globe in a patient with genetically confirmed type 1 Stickler syndrome. METHODS: Histological and electron microscopic examinations were performed on the enucleated globe from the proband of a pedigree with type 1 Stickler syndrome. Linkage analysis was carried out using polymorphic markers flanking the COL2A1 gene and the mutation was identified by direct sequencing. RESULTS: The significant retinal abnormality was incarceration of vitreous collagen within glial strands on the inner surface of an atrophic and gliotic detached retina. The incarcerated collagenous layers contained glial cells and extended from the retina to form strands, some of which contributed to a retrolental membrane. Mutation screening detected a C to T mutation in exon 47 that inserted a premature termination codon into the reading frame of the mRNA. Sequence analysis of three of the four affected children confirmed that they were also heterozygous for the base change. The youngest child's DNA was not analysed. CONCLUSIONS: The study represents the first evidence of abnormal interactions between pathological vitreous collagen and the inner retina in a patient with type 1 Stickler syndrome with a confirmed mutation in the COL2A1 gene.

Bacterial Peptide deformylase inhibitors: a new class of antibacterial agents.

Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth but is not required by mammalian cells. Thus, it represents a selective and promising target for the development of new antibacterial agents. Since deformylase inhibitors have yet to be used clinically as antibacterial drugs, compounds targeting this enzyme should avoid cross-resistance with currently used antibacterial agents. The PDF enzyme is a ferrous ion-containing metallohydrolase, but a nickel-containing surrogate is routinely used in the laboratory for testing inhibitors due to its better stability. Enzymes from several bacterial species have been cloned and both their three-dimensional structures and co-crystal structures with bound inhibitor have been determined. As a metallo enzyme, PDF lends itself to the well-precedented mechanism-based rational drug design approach. Using structural and mechanistic information together with high throughput screening, several types of potent PDF inhibitors have been identified. PDF inhibitors identified to date share a common structural feature of a "chelator + peptidomimetic" scaffold. Although compounds with many different chelators inhibit the cell free enzyme, only compounds containing hydroxamic acid or N-formyl hydroxylamine exhibit appreciable antibacterial activity. Several lead inhibitors have demonstrated in vivo efficacy and an excellent safety profile. Two PDF inhibitors, VIC-104959 (LBM415) and BB-83698, have progressed to Phase I clinical trials. In this review, different PDF inhibitors are compared and their biological activities are discussed. Structure-activity relationships have been established and the implications of this work in the design of future PDF inhibitors are considered.

Peptide deformylase inhibitors as antibacterial agents: identification of VRC3375, a proline-3-alkylsuccinyl hydroxamate derivative, by using an integrated combinatorial and medicinal chemistry approach.

Peptide deformylase (PDF), a metallohydrolase essential for bacterial growth, is an attractive target for use in the discovery of novel antibiotics. Focused chelator-based chemical libraries were constructed and screened for inhibition of enzymatic activity, inhibition of Staphylococcus aureus growth, and cytotoxicity. Positive compounds were selected based on the results of all three assays. VRC3375 [N-hydroxy-3-R-butyl-3-(2-S-(tert-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl)propionamide] was identified as having the most favorable properties through an integrated combinatorial and medicinal chemistry effort. This compound is a potent PDF inhibitor with a K(i) of 0.24 nM against the Escherichia coli Ni(2+) enzyme, possesses activity against gram-positive and gram-negative bacterial pathogens, and has a low cytotoxicity. Mechanistic experiments demonstrate that the compound inhibits bacterial growth through PDF inhibition. Pharmacokinetic studies of this drug in mice indicate that VRC3375 is orally bioavailable and rapidly distributed among various tissues. VRC3375 has in vivo activity against S. aureus in a murine septicemia model, with 50% effective doses of 32, 17, and 21 mg/kg of body weight after dosing by intravenous (i.v.), subcutaneous (s.c.), and oral (p.o.) administration, respectively. In murine single-dose toxicity studies, no adverse effects were observed after dosing with more than 400 mg of VRC3375 per kg by i.v., p.o., or s.c. administration. The in vivo efficacy and low toxicity of VRC3375 suggest the potential for developing this class of compounds to be used in future antibacterial drugs.

The natural history and treatment of rupture of the anterior cruciate ligament in children and adolescents. A prospective review.

A total of 60 children and adolescents with rupture of the anterior cruciate ligament (ACL) was seen between 1980 and 1990. Observation of the 23 patients who were treated conservatively revealed that the natural history of the injury resulted in severe instability and poor function of the knee. Associated meniscal tears were present in 15 knees. Three osteochondral fractures occurred and osteoarthritic changes developed in ten knees. In 1990 therefore we introduced reconstruction of the ACL with a four-strand hamstring graft using an anatomical placement with transphyseal tunnels and anchorage well away from the growth plate. Over a period of nine years, 47 knees underwent reconstruction. The mean follow-up was 49 months (12 to 96). No child suffered physeal damage or leg-length discrepancy. The results were satisfactory in 77% and there was little difference between patients treated before the adolescent growth spurt and those treated during or after this time. These results, however, were not as good as those seen in adults during the same period.