Putting genetic interactions in context through a global modular decomposition

Genetic interactions provide a powerful perspective into gene function, but our knowledge of the specific mechanisms that give rise to these interactions is still relatively limited. The availability of a global genetic interaction map in Saccharomyces cerevisiae, covering ～30% of all possible double mutant combinations, provides an unprecedented opportunity for an unbiased assessment of the native structure within genetic interaction networks and how it relates to gene function and modular organization. Toward this end, we developed a data mining approach to exhaustively discover all block structures within this network, which allowed for its complete modular decomposition. The resulting modular structures revealed the importance of the context of individual genetic interactions in their interpretation and revealed distinct trends among genetic interaction hubs as well as insights into the evolution of duplicate genes. Block membership also revealed a surprising degree of multifunctionality across the yeast genome and enabled a novel association of VIP1 and IPK1 with DNA replication and repair, which is supported by experimental evidence. Our modular decomposition also provided a basis for testing the between-pathway model of negative genetic interactions and within-pathway model of positive genetic interactions. While we find that most modular structures involving negative genetic interactions fit the between-pathway model, we found that current models for positive genetic interactions fail to explain 80% of the modular structures detected. We also find differences between the modular structures of essential and nonessential genes.     

The presence,characterization and prognosis of coronary plaques among patients with zero coronary calcium scores

Patients with coronary artery calcium (CAC) scores of zero are generally considered not to have atherosclerosis. Recent studies involving computed tomography coronary angiography (CTCA) challenge this assumption. This goal of the present study is to assess the frequency, morphology, location, and the prognosis of patients with plaque detected on CTCA and zero CAC. 1,119 patients (51 ± 12 years, 52% male) with a zero CAC score during CTCA study were retrospectively identified. The CTCA studies were assessed for the presence, morphology, location and severity of all coronary plaques. All-cause mortality was assessed. The prevalence of coronary plaque was 13% (147 patients). Among the 212 plaques identified 154 (73%) were non-calcified, 28 (13%) were calcified, and 30 (14%) were of mixed morphology. Notably, ≥70% stenosis was noted among only 0.4% of all patients. ROC analysis revealed that coronary artery disease risk factors did not add to the prediction of plaque among our patients. Over a mean follow-up of 2.5 ± 0.6 years there were 4 deaths (0.4%), all in patients without coronary plaque on CTCA. The presence of coronary plaque is not uncommon among patients with zero CAC scores. These plaques were rarely associated with hemodynamically significant stenoses and were associated with an excellent prognosis. Clinical factors do not appear to be useful in predicting which patients with zero CAC scores have undetected coronary plaque.     

Evaluation of Vitreous Substitutes in Managing Complicated Vitreo-retinal Surgeries

Background

Vitreous substitutes presently in use for intraoperative tamponade are perfluorocarbon liquids (PFCL) and for post operative tamponade are silicon oil (SO), sulphur hexafluoride (SF₆) and perfluorocarbon gas (PFC). Several factors are important for a thorough understanding of each of these vitreous substitutes. The absorption or necessity for removal, indications for use (including clinical studies and special surgical methods), additives and complications of use have to be considered.

Methods

Three port standard pars plana vitrectomy was performed in 60 consecutive cases requiring intra-vitreal intervention. PFCL was used intra-operatively in 30 cases (PFCL group and X group). The eyes were implanted with SO (silicon oil subgroup), PFC (C₃F₈ sub-group) and SF₆ (SF₆ sub-group) in twenty cases each. Apart from best corrected visual acuity (BCVA), the retinal status and the longevity of gas when used, changes and reaction in both the anterior and posterior segments were noted.

Result

The difference of postoperative BCVA in the PFCL and non-PFCL groups was statistically significant with p < 0.001. In both the PFCL and non-PFCL groups the difference between preoperative and postoperative BCVA was statistically significant with p < 0.0001. All three vitreous substitutes studied are effective given the case where they had been utilised.

Conclusion

PFCL is invaluable in the management of complicated retinal detachment (RD). Where a vitreous microsurgery is indicated, the visual outcome is good. SF₆ is useful for short-term tamponade. Silicon oil and C₃F₈ are useful for longer tamponade.Key Words: Tamponade, Perfluorocarbon liquids, Silicon oil, Sulphur hexafluoride, Perfluorocarbon gas, Retinal detachment     

5-Fluoro-Uracil and Low Molecular Weight Heparin in the Management of Proliferative Vitreo-retinopathy

Background

Proliferative vitreo-retinopathy (PVR) is the most common cause of failed repair of a primary rhegmatogenous retinal detachment (RRD). The success rates for the surgery of complicated RRD has doubled with improved vitreous techniques from 35–40% to approximately 65–75% at six months. However, despite these advances, recurrent vitreo-retinal traction leads to re-detachment in more than one-fourths of the initially successful cases. The use of adjunctive treatments to prevent cellular proliferation holds promise for the prevention of PVR or recurrences after surgery. One focus has been on the use of intra-vitreal antimetabolites to prevent the occurrence of PVR.

Methods

Thirty patients of complicated retinal detachment associated with PVR, C1 or more were managed by vitreo-retinal (VR) surgery with the addition of 250 μg / ml of 5-fluorouracil (5FU) and 1 IU / ml of low molecular weight heparin (LMWH) to the vitreous infusion. The patients were examined for any evidence of PVR till 180 days as also for any systemic or other ophthalmic complication.

Result

Out of the 30 cases in the study group, 25 (83.34%) cases had retinal settlement at the end of six weeks, which is similar to the outcomes of conventional VR surgery. There was no case of any serious complication.

Conclusion

The addition of LMWH and 5FU did not enhance the outcome of VR surgery.Key Words: Proliferative vitreo-retinopathy, Rhegmatogenons retinal detachment, 5-fluorouracil, Low molecular weight heparin     

A correlative study of gliomas usingIn vivo bromodeoxyuridine labeling index and computer-aided malignancy grading

An in vivo bromodeoxyuridine (BrdU) labeling index (LI) was estimated in 43 cases of astrocytic tumors and mixed gliomas by one hour intra-operative intravenous infusion at a dose of 200 mg/m2 and correlated with (a) histological grading using a computer aided malignancy classifier TESTAST-268; and (b) histological typing using WHO classification. The lowest BrdU LI was seen in pilocytic and gemistocytic astrocytomas followed by astrocytomas, anaplastic astrocytomas and glioblastoma multiforme in that order. Mixed oligoastrocytomas followed the pattern of their astrocytic counterparts. Tumors of similar histological type showed different BrdU LI values especially amongst astrocytomas and glioblastomas. A statistically significant difference in the BrdU LI was also noted between the higher TESTAST grades of astrocytomas (T III and IV) versus the lower TESTAST grades (T II). Unlike earlier reports in literature, in the present study the category of BrdU LI of <1 contained no case of anaplastic astrocytoma or glioblastoma multiforme (TESTAST grades III and IV). Likewise, the category of BrdU LI >5 contained only anaplastic astrocytoma and glioblastoma multiforme (TESTAST grades III and IV). Maximum spread of cases was seen in the BrdU LI category of 1-5, not only in terms of histological types but also TESTAST grades. Thus there appeared to be a positive trend of increasing BrdU LI values both with histological types and increasing TESTAST grades. Further, an interesting observation was that by using a combination of TESTAST grades and BrdU LI, the histologically homogenous glioblastoma group could be further subdivided into 4 categories which showed a trend towards prognostic correlation. Thus, this study though preliminary with number of cases being small in some groups, highlights the possible usefulness of combined histological typing, TESTAST grading and in vivo BrdU LI for prognostication of gliomas especially glioblastoma multiforme.