Rectovaginal Fistulas Not Involving the Rectovaginal Septum Should Be Treated Like Anal Fistulas: A New Concept and Proposal for a Reclassification of Rectovaginal Fistulas.

Background: Many rectovaginal fistulas(RVF), especially low RVF, do not involve/penetrate the RV-septum, but due to lack of proper nomenclature, such fistulas are also managed like RVF (undertaking repair of RV-septum) and inadvertently lead to the formation of a high RVF (involving RV-septum) in many cases. Therefore, REctovaginal Fistulas, Not Involving the Rectovaginal Septum, should be Treated like Anal fistulas(RENISTA) to prevent any risk of injury to the RV septum. This concept(RENISTA) was tested in this study. Methods: RVFs not involving RV-septum were managed like anal fistulas, and the RV-septum was not cut/incised. MRI, objective incontinence scoring, and anal manometry were done preoperatively and postoperatively. High RVF (involving RV-septum) were excluded. Results: Twenty-seven patients with low RVF (not involving RV-septum) were operated like anal fistula[age:35.2±9.2 years, median follow-up-15 months (3-36 months)]. 19/27 were low fistula[<1/3 external anal sphincter(EAS) involved] and fistulotomy was performed, whereas 8/27 were high fistula (>1/3 EAS involved) and underwent a sphincter-sparing procedure. Three patients were excluded. The fistula healed well in 22/24 (91.7%) patients and did not heal in 2/24 (8.3%). The healing was confirmed on MRI, and there was no significant change in mean incontinence scores and anal pressures on tonometry. RV-septum injury did not occur in any patient. Conclusions: RVF not involving RV-septum were managed like anal fistulas with a high cure rate and no significant change in continence. RV-septum injury or formation of RVF with septum involvement did not occur in any patient. The RENISTA concept was validated in the present study. A new classification was developed to prevent any inadvertent injury to the RV-septum.

Hsf1 and the molecular chaperone Hsp90 support a 'rewiring stress response' leading to an adaptive cell size increase in chronic stress.

Cells are exposed to a wide variety of internal and external stresses. Although many studies have focused on cellular responses to acute and severe stresses, little is known about how cellular systems adapt to sublethal chronic stresses. Using mammalian cells in culture, we discovered that they adapt to chronic mild stresses of up to two weeks, notably proteotoxic stresses such as heat, by increasing their size and translation, thereby scaling the amount of total protein. These adaptations render them more resilient to persistent and subsequent stresses. We demonstrate that Hsf1, well known for its role in acute stress responses, is required for the cell size increase, and that the molecular chaperone Hsp90 is essential for coupling the cell size increase to augmented translation. We term this translational reprogramming the 'rewiring stress response', and propose that this protective process of chronic stress adaptation contributes to the increase in size as cells get older, and that its failure promotes aging.

New objective scoring system to clinically assess fecal incontinence.

BACKGROUND: Several scoring systems are used to assess fecal incontinence (FI), among which, the most commonly used are Wexner and Vaizey's scoring systems. However, there are significant lacunae in these scoring systems, due to which they are neither accurate nor comprehensive. AIM: To develop a new scoring system for FI that is accurate, comprehensive, and easy to use. METHODS: A pro forma was made in which six types of FI were included: solid, liquid, flatus, mucous, stress, and urge. The weight for each FI was determined by asking a group of patients and laypersons to give a disability score to each type of FI from 0 to 100 (0- least, 100- maximum disability). The disability was assessed on a modified EQ-5D+ (EuroQol) description system, 4D3L (4 dimensions and 3 levels) for each FI. The average score of each FI was calculated, divided by 10, and rounded off to determine the weight of each FI type. The scores for the three levels of frequency of each FI were assigned as never = 0 (No episode of FI ever), occasional = 1 (≤ 1 episode of FI/ wk), and common = 2 (> 1 episode of FI/ wk), and was termed as frequency score. The score for each FI would be derived by multiplying the frequency score and the weight for that FI type. In the second phase of the study, a group of colorectal surgeons was asked to rank the six FI types in order of severity, and their ranking was compared with the patient and laypersons' rankings. RESULTS: Fifty patients and 50 laypersons participated in the study. The weight was assigned to each FI (solid-8, liquid-8, urge-7, flatus-6, mucus-6, and stress-5), and an new scoring system was formulated. The maximum possible score was 80 (total incontinence), and the least 0 (no incontinence). The surgeons' ranking of FI severity did not correlate well with patients' and laypersons' rankings of FI, highlighting that surgeons and patients may perceive the severity of FI differently. CONCLUSION: A new scoring system for FI was formulated, which was simple, logical, comprehensive, and easy to use, and eliminated previous shortcomings. Patients' and surgeons' perceptions of FI severity of FI did not correlate well.

Treatment of Keloids with Surgery and Immediate Postoperative Radiotherapy: Knowledge Gained Over 17 Years.

Background The treatment of keloidal scars with radiotherapy has been practiced for more than a century. Radiotherapy post-surgery has been deemed necessary and effective in preventing recurrence but still, no clear guidelines exist as to the best modality of radiotherapy, the ideal dose, and the time it should be given for keloidal scars. The purpose of this study is to confirm the effectiveness of this treatment and address these issues. Methods Since 2004, 120 patients presenting with keloidal scars were seen by the author. Out of them, 50 were managed with surgery followed by HDR brachytherapy/electron beam radiotherapy delivering 2000 rads to the scar within 24 hours of surgery. Patients were followed up for at least 18 months to assess the scar status and the recurrence of keloids. Recurrence was defined as the appearance of a nodule or an obvious return of the keloid within 1 year of treatment. Results Three patients developed a nodule in the scar, which was deemed a recurrence, making an incidence of 6%. There was no major problem after immediate postoperative radiotherapy. Five patients had delayed healing at 2 weeks and a hypertrophic scar was noted in five patients at 4 weeks that settled with conservative measures. Conclusion Treating the vexing problem of keloids with surgery and immediate postoperative radiotherapy is safe and effective. We recommend that this be adopted as the standard treatment in keloid management.

Network-informed discovery of multidrug combinations for ERα+/HER2-/PI3Kα-mutant breast cancer.

Breast cancer is a persistent threat to women worldwide. A large proportion of breast cancers are dependent on the estrogen receptor α (ERα) for tumor progression. Therefore, targeting ERα with antagonists, such as tamoxifen, or estrogen deprivation by aromatase inhibitors remain standard therapies for ERα + breast cancer. The clinical benefits of monotherapy are often counterbalanced by off-target toxicity and development of resistance. Combinations of more than two drugs might be of great therapeutic value to prevent resistance, and to reduce doses, and hence, decrease toxicity. We mined data from the literature and public repositories to construct a network of potential drug targets for synergistic multidrug combinations. With 9 drugs, we performed a phenotypic combinatorial screen with ERα + breast cancer cell lines. We identified two optimized low-dose combinations of 3 and 4 drugs of high therapeutic relevance to the frequent ERα + /HER2-/PI3Kα-mutant subtype of breast cancer. The 3-drug combination targets ERα in combination with PI3Kα and cyclin-dependent kinase inhibitor 1 (p21). In addition, the 4-drug combination contains an inhibitor for poly (ADP-ribose) polymerase 1 (PARP1), which showed benefits in long-term treatments. Moreover, we validated the efficacy of the combinations in tamoxifen-resistant cell lines, patient-derived organoids, and xenograft experiments. Thus, we propose multidrug combinations that have the potential to overcome the standard issues of current monotherapies.

An incarcerated epigastric hernia containing stomach.

Most epigastric hernia contains preperitoneal fat or the omentum. Intraabdominal organ herniation is rare and, if present, contains mostly small bowel. Incarcerated epigastric hernia having the stomach as content is infrequent, and only one case has been reported in the literature so far. Herein, we report a rare case of incarcerated epigastric hernia that contains the stomach and was managed with emergency hernioplasty.

Leaping liquid crystal elastomers.

Snap-through mechanisms are pervasive in everyday life in biological systems, engineered devices, and consumer products. Snap-through transitions can be realized in responsive materials via stimuli-induced mechanical instability. Here, we demonstrate a rapid and powerful snap-through response in liquid crystalline elastomers (LCEs). While LCEs have been extensively examined as material actuators, their deformation rate is limited by the second-order character of their phase transition. In this work, we locally pattern the director orientation of LCEs and fabricate mechanical elements with through-thickness (functionally graded) modulus gradients to realize stimuli-induced responses as fast as 6 ms. The rapid acceleration and associated force output of the LCE elements cause the elements to leap to heights over 200 times the material thickness. The experimental examination in functionally graded LCE elements is complemented with computational evaluation of the underlying mechanics. The experimentally validated model is then exercised as a design tool to guide functional implementation, visualized as directional leaping.

Phosphorylation of the Hsp90 Co-Chaperone Hop Changes its Conformational Dynamics and Biological Function.

The molecular chaperones Hsp90 and Hsp70 and their regulatory co-chaperone Hop play a key role at the crossroads of the folding pathways of numerous client proteins by forming fine-tuned multiprotein complexes. Alterations of the biomolecules involved may functionally impact the chaperone machinery: here, we integrate simulations and experiments to unveil how Hop conformational fitness and interactions can be controlled by the perturbation of just one residue. Specifically, we unveil how mechanisms mediated by Hop residue Y354 control Hop open and closed states, which affect binding of Hsp70/Hsp90. Phosphorylation or mutation of Hop-Y354 are shown to favor structural ensembles that are indeed not optimal for stable interactions with Hsp90 and Hsp70. This disfavors cellular accumulation of the stringent Hsp90 clients glucocorticoid receptor and the viral tyrosine kinase v-Src, with detrimental effects on v-Src activity. Our results show how the post-translational modification of a specific residue in Hop provides a regulation mechanism for the larger chaperone complex of which it is part. In this framework, the effects of one single alteration are amplified at the cellular level through the perturbation of protein-interaction networks.

Professor Leslie H. Blumgart-Pioneering Hepatopancreaticobiliary Surgeon: a Tribute.

Leslie Harold Blumgart was the surgeon behind making Hepatopancreaticobiliary surgery a speciality and his recent demise will always leave a void in that field. He was the person who classified anatomical variations in the biliary tract and devised a special anastomotic technique to decrease the rate of postoperative pancreatic duct fistula after Whipple's pancreaticoduodenectomy. His contribution in managing hepatobiliary oncology cases with chemotherapy and radiotherapy was also significant. No wonder, he was designated as the "living legend" by the International Hepatopancreaticobiliary Association.

Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life.

The cytosolic molecular chaperone Hsp90 is essential for eukaryotic life. Although reduced Hsp90 levels correlate with aging, it was unknown whether eukaryotic cells and organisms can tune the basal Hsp90 levels to alleviate physiologically accumulated stress. We have investigated whether and how mice adapt to the deletion of three out of four alleles of the two genes encoding cytosolic Hsp90, with one Hsp90ß allele being the only remaining one. While the vast majority of such mouse embryos die during gestation, survivors apparently manage to increase their Hsp90ß protein to at least wild-type levels. Our studies reveal an internal ribosome entry site in the 5' untranslated region of the Hsp90ß mRNA allowing translational reprogramming to compensate for the genetic loss of Hsp90 alleles and in response to stress. We find that the minimum amount of total Hsp90 required to support viability of mammalian cells and organisms is 50-70% of what is normally there. Those that fail to maintain a threshold level are subject to accelerated senescence, proteostatic collapse, and ultimately death. Therefore, considering that Hsp90 levels can be reduced ≥100-fold in the unicellular budding yeast, critical threshold levels of Hsp90 have markedly increased during eukaryotic evolution.