Association between facial measurements and polymorphisms in human epidermal growth factor and transforming growth factor ß1.

The aim of the study was to evaluate the association between genetic polymorphisms in human epidermal growth factor (EGF) (rs4444903) and transforming growth factor ß1 - (TGF-ß1) (rs1800470) with facial measurements in patients with dentofacial deformities. A total of 144 adult patients with dentofacial deformities were included. Facial linear and angular measurements were traced in lateral cephalometric radiographs used Dolphin 2D software. Cells from oral mucosa were collected for DNA to be extracted. The polymorphisms were genotyped using real-time polymerase chain reaction (PCR). Probabilites of less than 0.05 were accepted as significant. The rs4444903 heterozygous patients had a decrease in the mandibular length (p=0.043) and the length of the mandibular base (p=0.008), and homozygous A patients also had a reduction in the length of the mandibular base (p=0.013) compared with homozygous G patients. Patients AG had an increase in measurement of the anterior facial height (p=0.032) and in ANS-Me distance (p=0.022) when compared with homozygous A. To the rs1800470, heterozygous patients had an increase in the length of the mandibular base (p=0.043) when compared with homozygous A. Heterozygous AG patients had an increase in angular measurements in TGF-ß1 polymorphism for the upper gonial angle, when compared with the homozygous AA (p=0.032). Genetic polymorphisms in EGF and TGF-ß1 are associated with facial measurements in a Brazilian population of patients with dentofacial deformities.

Predictors of outcome for patients with severe respiratory failure requiring non invasive mechanical ventilation.

OBJECTIVE: Failure to identify patients in whom non-invasive ventilation (NIV) would be unsuccessful may cause inappropriate delay in intubation. Aim of this study was to determine predictors of NIV failure. PATIENTS AND METHODS: We retrospectively evaluated COPD patients, undergoing NIV for at least 12h because of hypercapnic acute respiratory failure. Univariable and multivariable analyses were performed on: age, gender, APACHE II and GCS, gas exchange at admission, during NIV and at discharge/death, length of stay. ROC analysis for pH START and APACHE II were performed. RESULTS: Among 201 individuals enrolled, NIV failed in 50. In the logistic regression model only APACHE II was found to have an independent effect on the outcome (p < 0.0001, OR 1.179, 95% CI 1.101-1.263 as quantitative variable; p < 0.0001, OR 3.753, 95% CI 1.798-7.835, as qualitative variable, > 20.5). CONCLUSIONS: APACHE II may be a crucial parameter in predicting NIV failure; further multicentric studies are needed to better define NIV indications.

Efficacy of pirfenidone for idiopathic pulmonary fibrosis: An Italian real life study.

BACKGROUND: In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. METHODS: We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. RESULTS: At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. CONCLUSIONS: In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease.

A combined therapeutic approach in progressive idiopathic pulmonary fibrosis-pirfenidone as bridge therapy for ex vivo lung transplantation: a case report.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial pneumonia of unknown etiology, which is associated with the histopathologic pattern of usual interstitial pneumonia (UIP) and leads to a progressive decrease of respiratory function. The present article describes a case of a 62-year-old ex-smoker referred to our hospital because of IPF. After 2 years of follow-up, the subject experienced a significant worsening of pulmonary function and was enrolled in a lung transplantation program. Afterward, a pharmacological treatment with pirfenidone was started, achieving a stabilization of respiratory function. The patient underwent a single lung transplantation by means of a normothermic ex vivo lung perfusion (EVLP) approach according to the Toronto model. At 20-month evaluation the subject's respiratory function was significantly improved, and quality of life was considerably ameliorated. We believe that an integrated multidisciplinary approach should be considered a key option for the treatment of individuals with IPF.

Ruthenium-106 eye plaque brachytherapy in the conservative treatment of uveal melanoma: a mono-institutional experience.

BACKGROUND: Traditional treatment for uveal melanoma is the enucleation of the eye with outcomes cosmetically unacceptable and loss of useful vision. Plaque brachytherapy, compared to enucleation, had the advantage to preserve the eye with outcomes cosmetically acceptable and preservation of vision. PATIENTS AND METHODS: From July 1990 to December 2009 one hundred forty-two (142) patients (51 males and 91 females) with small to medium uveal melanoma were treated with 106Ru plaque brachytherapy. The patients underwent a complete staging before brachytherapy with indirect ophthalmoscopy and ultrasounds. Mean tumour thickness was 3.26 mm (1.6-6 mm). The dose scheduled was 80-100 Gy to the apex with a maximum dose of 800 Gy to the sclera. RESULTS: One hundred forty-two have been treated, nine patients had lost the follow-up and drop out; 133 patients were assessed. Mean follow-up was 7.7 years (6 months-18 years). The overall survival at 5, 10 and 15 years was 92%, 85% and 78% respectively. Cancer fee survival was 95%, 90% and 83%, respectively at 5, 10 and 15 year. Radiation-induced toxicity was represented in 47 patients with a 5 year actuarial survival rate free from complications of 54%. CONCLUSIONS: 106Ru plaque brachytherapy is a valid approach for treatment of uveal melanoma. This technique is efficacy and safe, with a low toxicity profile.

Inhibiting oncogenic signaling by sorafenib activates PUMA via GSK3ß and NF-κB to suppress tumor cell growth.

Aberrant Ras/Raf/MEK/ERK signaling is one of the most prevalent oncogenic alterations and confers survival advantage to tumor cells. Inhibition of this pathway can effectively suppress tumor cell growth. For example, sorafenib, a multi-kinase inhibitor targeting c-Raf and other oncogenic kinases, has been used clinically for treating advanced liver and kidney tumors, and also has shown efficacy against other malignancies. However, how inhibition of oncogenic signaling by sorafenib and other drugs suppresses tumor cell growth remains unclear. In this study, we found that sorafenib kills cancer cells by activating PUMA (p53-upregulated modulator of apoptosis), a p53 target and a BH3-only Bcl-2 family protein. Sorafenib treatment induces PUMA in a variety of cancer cells irrespective of their p53 status. Surprisingly, the induction of PUMA by sorafenib is mediated by IκB-independent activation of nuclear factor (NF)-κB, which directly binds to the PUMA promoter to activate its transcription. NF-κB activation by sorafenib requires glycogen synthase kinase 3ß activation, subsequent to ERK inhibition. Deficiency in PUMA abrogates sorafenib-induced apoptosis and caspase activation, and renders sorafenib resistance in colony formation and xenograft tumor assays. Furthermore, the chemosensitization effect of sorafenib is dependent on PUMA, and involves concurrent PUMA induction through different pathways. BH3 mimetics potentiate the anti-cancer effects of sorafenib, and restore sorafenib sensitivity in resistant cells. Together, these results demonstrate a key role of PUMA-dependent apoptosis in therapeutic inhibition of Ras/Raf/MEK/ERK signaling. They provide a rationale for manipulating the apoptotic machinery to improve sensitivity and overcome resistance to the therapies that target oncogenic kinase signaling.

Macular coloboma in siblings affected by different phenotypes of retinitis pigmentosa.

Purpose To report the clinical association between macular coloboma (early-onset macular dystrophies/atrophic changes) and different phenotypes of retinitis pigmentosa (RP). Methods Three young-adult siblings, two males and one female, were retrospectively studied. These patients underwent two complete ophthalmologic examinations (27-month follow-up), including orthoptic evaluation, colour vision test, visual field, corneal topography, electronystagmography, fluorescein angiography, and electroretinography. Eye check, automated visual field test, and complete electroretinographic study were also conducted on other asymptomatic members of the same family. Results All symptomatic siblings were affected by manifest congenital nystagmus, poor visual acuity, and progressive visual field impairment in both eyes, bilaterally presenting macular coloboma associated with three different RP patterns: classic RP; mild dystrophy of the retinal pigment epithelium, associated with subnormal electroretinographic findings (subclinical form of RP); and sector RP. The ophthalmologic reports regarding their deceased father documented that he had suffered from the same alterations of ocular movements and visual performances diagnosing, in both eyes, extensive atrophic changes of the macular area completely surrounded by pigmented bone spicules (RP-type tapeto-retinal dystrophy). The other investigated relatives did not show any specific and/or significant ocular disorder. Conclusions In these three adult members of the same family, the concomitance between macular coloboma and different intrafamilial RP phenotypes is described. This association represents an autosomal dominant clinical entity, hitherto observed only in non familial sporadic cases.Eye (2004) 18, 421-428. doi:10.1038/sj.eye.6700689

Quantitative evaluation of the retinal venous tortuosity in chronic anaemic patients affected by beta-thalassaemia major.

AIMS: Retinal venous tortuosity (RVT) is a common finding in patients affected by different forms of chronic anaemia. The aims of this study were to quantify RVT in anaemic patients with beta-thalassaemia major and to verify whether it is related to some of the following parameters: patient's age, ferritin plasma level, and Desferrioxamine (DFX) daily dosage. METHODS: A retrospective study was carried out. In total, 36 consecutive thalassaemic patients, treated with polytransfusion regimen and DFX, were age- and sex-matched with a control group of 36 normal subjects. All subjects bilaterally underwent red-free fundus photography, centred on the optic disc. The four main retinal veins were measured with a computer-assisted method. RESULTS: Mean venous length in the thalassaemic group was significantly greater than that observed in the control group (P <0.001). In thalassaemic patients, no significant correlations between retinal venous length and, respectively, plasma ferritin level and DFX daily dosage were documented. Statistical analysis demonstrated a very significant association between patient's age and increased RVT only in thalassaemic patients (P <0.001). CONCLUSIONS: Our findings demonstrate that patients with beta-thalassaemia major have increased RVT, as compared to normal subjects. In this selected anaemic population, patient's age, closely related to anaemia duration, is the only variable responsible for the RVT increment. This clinical sign indicates a long-standing duration of anaemia.

Management of incontinentia pigmenti: a case of monolateral preretinal fibrovascular proliferations adjacent to snail-track degeneration areas.

PURPOSE: To report a case of monolateral preretinal fibrovascularproliferations in a young adult woman, who had suffered from incontinentia pigmenti (IP) during her first month of life. METHODS: Case report. RESULTS: Circumscribed preretinal fibrovascular proliferations, adjacent to a mid-peripheral area of snail track degeneration, were occasionally diagnosed in the left eye of an asymptomatic 18-year-old white female. Careful ocular examination did not reveal any cause of the monolateral vascular abnormalities observed in the posterior segment. A detailed medical history brought to light that the patient has suffered infantile IP, like four other females in her family. The patient did not present any evident malformation of teeth, nails, skeleton or hair. A cytogenetic linkage study documented a chromosomal aberration in the Xq28 band, which confirmed the diagnosis of familial IP (type 2). The fluorescein angiography findings clearly illustrated the minimal retinal involvement in the course of IP. CONCLUSIONS: This case shows that a wide range of etiologies must be considered in patients presenting monolateral preretinal fibrovascular proliferations. To correctly manage these uncommon, inherited or acquired, retinal diseases it is better to do a mid-term follow-up, rather than operate immediately, and this enabled us to observe the natural course of the lesion, while awaiting a definitive diagnosis.

Bilateral central serous chorioretinopathy in a patient treated with systemic cortico-steroids for non-Hodgkin lymphoma.

PURPOSE: To describe the concomitant occurrence of systemic cortico-steroid treatment and the development of bilateral central serous chorioretinopathy (CSC), which promptly regressed after the reduction of the drug dosage, up to its scheduled withdrawal. METHODS: Case report. RESULTS: A 46-year-old white male, with a history of monolateral CSC, had a non-Hodgkin lymphoma on his right cheek. Soon after surgical excision of the tumoral lesion, he received a standard post-operative regimen of decreasing intramuscular betamethasone for 25 days, followed by 10 day's withdrawal, then cycles of intravenous cyclophosphamide and vincristine, followed by 7-day oral prednisone, repeated monthly for three months. Fluorescein angiographies at the end of the first oral cortico-steroid cycle and before starting the second, documented the occurrence of bilateral CSC and its regression, which were chronologically related respectively to the cortico-steroid administration and withdrawal. CONCLUSIONS: This case further demonstrates that systemic cortico-steroids can be responsible for the occurrence of CSC. The patient's history should always be checked for any previous CSC episodes. In these subjects, periodical ophthalmoscopic examination is essential to discover early or asymptomatic steroid-related CSC patterns, to prevent complications of the disease.

Recurrent central retinal vein occlusion in a young thrombophilic patient with factor V Leiden mutation.

PURPOSE: To investigate the cause of recurrent central retinal vein occlusion in a 26-year-old white woman. METHODS: Case report. Complete blood analyses were done, including HLA tissue typing, immunoserologic and coagulation tests, with cardiovascular and capillaroscopy investigations. Factor V:R506Q and prothrombin 20210 GIA mutations were checked by polymerase chain reaction and restriction enzyme analysis. RESULTS: DNA analysis showed the patient to be heterozygous for factor V:R506Q mutation. During a follow-up of 18-months, after starting anticoagulant therapy, the patient had not suffered from any other ocular or systemic occlusive vascular accident. CONCLUSIONS: The R506Q factor V gene mutation may be associated with recurrent central retinal vein occlusions. Genetic investigation should be promptly recommended in thrombotic patients to establish a specific preventive treatment.

New findings in the Parry-Romberg syndrome: a case report.

PURPOSE: To describe further findings in the Parry-Romberg syndrome that might contribute towards a better understanding of the disease. DESIGN: Case report. METHODS: The clinical history of a patient with the Parry-Romberg syndrome was studied, and fluorangiography and echography were carried out. RESULTS: Clinical observation revealed classic hemifacial atrophy; fluorescein angiography showed telangiectasis, light staining of the retina, and leakage from the largest telangiectasis and the optic disc vessels; echography showed shrinkage of the eyeball and thinning of the extraocular muscles. CONCLUSIONS: Enophthalmos in this disease is caused not only by progressive fat atrophy but also by shrinkage of the eyeball and thinning of the extraocular muscles; the shrinkage of the eyeball helps explain the presence of choroidal and retinal folding and hyperopia, confirming the primary involvement of connective tissue in this disease.

Effect of hinged lamellar keratotomy on postkeratoplasty eyes.

PURPOSE: To evaluate the effect of a hinged lamellar keratotomy on refraction, vision, and corneal topography of postkeratoplasty eyes with high-degree astigmatism. DESIGN: Noncomparative, interventional case series. PARTICIPANTS: A hinged lamellar keratotomy was performed on nine eyes of nine patients at least 9 months after penetrating keratoplasty and with high-degree astigmatism. All patients were spectacle and contact lens intolerant. INTERVENTION: A superiorly hinged lamellar keratotomy (corneal flap), 160 microm in thickness and 9 mm in diameter, was created on all eyes included in this study. Each patient was examined 1 day, 1 month, and 3 months after surgery. MAIN OUTCOME MEASURES: Uncorrected visual acuity, best spectacle-corrected visual acuity, refraction, computerized analysis of corneal topography. RESULTS: At each postoperative examination time, there was a significant reduction in both average spherical equivalent (P < 0.05) and average absolute value of astigmatism (P < 0.01) over mean preoperative values. The major changes were seen as early as 1 day after surgery, but both progression and regression of the effect were documented at later postoperative examinations. In all patients best spectacle-corrected acuity was maintained or improved after the procedure. Postoperatively, four patients could be successfully corrected either with spectacles (n = 2) or with gas-permeable contact lenses (n = 2). There were no surgical flap or corneal graft complications. CONCLUSIONS: Hinged lamellar keratotomy improves vision and refraction of postkeratoplasty eyes with high-degree astigmatism. In some cases it may be so effective as to make planned excimer laser treatment unnecessary.

The heterozygous 20210 G/A genotype prevalence in patients affected by central and branch retinal vein occlusion: a pilot study.

BACKGROUND: Several inherited conditions have been associated with an increased or decreased incidence of retinal vein occlusion (RVO). The A allele in the 20210 G/A prothrombin gene has been found to be associated with systemic venous thrombosis. The aim of this study has been to verify the prevalence of this mutation in patients affected by central RVO (CRVO) or branch RVO (BRVO). METHODS: A retrospective study was carried out on 100 consecutive patients suffering from RVO, more than 50 years old, unaffected by systemic diseases known to be associated with markedly increased RVO occurrence. We determined the frequency of this mutation by performing mutagenised amplification of exon 14 followed by restriction analysis of the amplified DNA fragment. RESULTS: The overall frequency of prothrombin 20210A allele in RVO patients was 6.0%. All heterozygous patients had suffered from CRVO. In this study subgroup, the frequency of the 20210 G/A prothrombin heterozygosis was 12.0%. The difference in the frequency of this the genetic variant between the CRVO and BRVO groups was statistically significant. None of the conventional RVO risk factors were statistically related to the occurrence of the disease in either the CRVO or the BRVO subgroup. CONCLUSION: The prevalence of the prothrombin 20210A mutation observed in CRVO patients is significantly higher than in the normal Italian population. Moreover, the prevalence is significantly greater in CRVO than in BRVO patients. These results raise the possibility that the prothrombin 20210A variant may be considered as a risk factor for CRVO.

Endokeratoplasty as an alternative to penetrating keratoplasty for the surgical treatment of diseased endothelium: initial results.

PURPOSE: To test the feasibility of a new surgical technique aimed at replacing diseased corneal endothelium while minimizing visual recovery time. DESIGN: Noncomparative, prospective, clinic-based, interventional case series. PARTICIPANTS: A total of seven patients with aphakic bullous keratopathy (n = 2), pseudophakic bullous keratopathy (n = 4), or Fuchs' corneal dystrophy (n = 1) participated. INTERVENTION: All patients underwent a surgical procedure including removal of the epithelium, creation of a 9.5-mm corneal flap, substitution of an underlying 6.5-mm button of deep stroma and endothelium with a 7.0-mm donor button, and suturing of the flap back into position using a 10-0 running nylon suture. In the two most recently operated patients, anterior lamella, 160 microm in thickness, was removed from the donor button before transplantation. MAIN OUTCOME MEASURES: Visual acuity, refraction, keratometry, corneal topography. RESULTS: All corneas were clear, and the surface reepithelialized within 4 weeks after surgery. Regular astigmatism of less than 4 diopters was recorded in all cases as early as 4 weeks after surgery. Epithelial interface ingrowth with extensive melting of the corneal flap was observed in one patient 3 months after surgery and was managed by removal of the flap and resuturing of the donor button. CONCLUSIONS: Endokeratoplasty represents a promising alternative to conventional penetrating keratoplasty for patients with diseased corneal endothelium.