Collagen cross-linking in thin corneas

Collagen cross-linking (CXL) has become the standard of care for progressive keratoconus, after numerous clinical studies have established its efficacy and safety in suitably selected eyes. The standard protocol is applicable in eyes which have a minimum corneal thickness of 400 μm after epithelial debridement. This prerequisite was stipulated to protect the corneal endothelium and intraocular tissues from the deleterious effect of ultraviolet-A (UVA) radiation. However, patients with keratoconus often present with corneal thickness of less than 400 μm and could have otherwise benefited from this procedure. A few modifications of the standard procedure have been suggested to benefit these patients without a compromise in safety. Transepithelial cross-linking, pachymetry-guided epithelial debridement before cross-linking, and the use of hypoosmolar riboflavin are some of the techniques that have been attempted. Although clinical data is limited at the present time, these techniques are worth considering in patients with thin corneas. Further studies are needed to scientifically establish their efficacy and safety.     

A multicentre,phase II trial of ofatumumab monotherapy in relapsed/progressive diffuse large B‐cell lymphoma

This international, multicentre phase II study was conducted to assess ofatumumab, a human anti‐CD20 monoclonal antibody, in patients with relapsed/progressive diffuse large B‐cell lymphoma (DLBCL) who were ineligible for autologous stem cell transplantation (TI) or who had relapse/progression after transplantation (PT). Eighty‐one patients received ofatumumab 300 mg intravenously (IV) on Day 1, followed by seven weekly IV infusions of 1000 mg. Patients in the TI and PT groups had received a median of 3 (range, 1–7) and 5 (range, 2–7) prior therapies, respectively. One‐third of patients did not respond to the last prior therapy, and 53% had failed two or more rituximab‐containing therapies. Overall response rate was 13% for the TI group (seven partial responses) and 8% for the PT group (two complete responses). Median progression‐free survival was 2·6 months, and median duration of response was 9·5 months. The most common Grade 3–4 adverse events were neutropenia (11%), leucopenia (6%), lymphopenia (6%) and thrombocytopenia (6%). Sixteen deaths have been reported, with disease progression as the most common cause of death. In conclusion, ofatumumab monotherapy was well tolerated and provided clinical benefit to some DLBCL patients in this study. This trial was registered at www.clinicaltrials.gov (NCT00622388).     

T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival

PURPOSE: Preoperative chemoradiation therapy is used widely in the treatment of rectal cancer. The predictive value of response to neoadjuvant remains uncertain. We retrospectively evaluated the impact of response to preoperative and, specifically, of T-level downstaging, nodal downstaging, and complete pathologic response after chemoradiation therapy on oncologic outcome of patients with locally advanced rectal cancer. METHODS: There were 88 patients with ultrasound Stage T3/T4 midrectal (n = 37) and low rectal (n = 51) cancers (63 males; mean age 62.6 years). All patients were treated by preoperative 5-fluorouracil-based chemotherapy and pelvic radiation followed by surgical resection in six weeks or longer (56 sphincter-preserving resections). RESULTS: T-level downstaging after neoadjuvant treatment was demonstrated in 36 (41 percent) of 88 patients, and complete pathologic response was observed in 16 (18 percent) of the 88. Of the 42 patients with ultrasound-positive nodes, 27 had no evidence of nodal involvement on pathologic evaluation (64 percent). The overall response rate (T-level downstaging or nodal downstaging) was 51 percent. At a median follow-up of 33 months, 86.4 percent of patients were alive. The overall recurrence rate was 10.2 percent (three patients had local and six had metastatic recurrences). Patients with T-level downstaging and complete pathologic response were characterized by significantly better disease-free survival (P = 0.03, P = 0.04) and better overall survival (P = 0.07, P = 0.08), according to Wilcoxons test comparing Kaplan-Meier survival curves. None of the patients with complete pathologic response developed recurrence or died during the follow-up period. CONCLUSION: T-level downstaging and complete pathologic response after preoperative chemoradiation therapy followed by definitive surgical resection for advanced rectal cancer resulted in decreased recurrence and improved disease-free survival. Advanced rectal cancers that undergo T-level downstaging and complete pathologic response after chemoradiation therapy may represent subgroups that are characterized by better biologic behavior.     

Crystal structure of a hydrophobic 19-residue peptide helix containing three centrally located D amino acids

The design of the synthetic 19-residue peptide Boc-Leu-Aib-Val-Ala-Leu5-Aib-Val-D-Ala-d-Leu-Leu10-Val-Phe-Val-Aib-D-Val15-Leu-Phe-Val-Val-OMe (Aib, alpha-aminoisobutyric acid; OMe, methyl ester) was intended to produce a crystalline peptide with independent helical and hairpin domains. The design was partially based on an octapeptide with the same sequence as residues 11-18 above, which was shown to fold into a beta-hairpin in the crystal. However, the crystal structure of the present peptide provided a surprising result. The conformation is the longest characterized right-handed alpha-helix, with as many as three internal d residues in the sequence. The completely helical structure was also unexpected, because beta-branched residues such as Val have a low propensity for helix formation in proteins. The helical peptides in the present structure assemble to form hydrophobic channels that accommodate five toluene molecules per peptide along the length of the channel. The structural results illustrate the similarity in energetics between helical and beta-hairpin conformations for peptides containing Aib residues. The crystallographic parameters for C107H179N19O22.3H2O.2.5 toluenes are: space group C2, a = 34.679(3) A, b = 12.866(1) A, c = 31.915(3) A, beta = 96.511(8) degrees, V = 14,148 A3, Z = 4, dcalc = 1.099 g/cm3, and agreement factor R1 = 10.2%.     

Prognostic value of QT interval and QT dispersion in patients with left ventricular systolic dysfunction: results from a cohort of 2265 patients with an ejection fraction of < or =40%

Background Increased QT interval and QT dispersion have been associated with higher mortality in population-based studies and in patients with myocardial infarction. However, the prognostic significance of these measurements in patients with left ventricular (LV) systolic dysfunction is not clear.Methods and Results Rate corrected QT interval (QTc) and QT dispersion (QTd) were measured by means of an automated method from digitized echocardiograms in 2265 patients with an LV ejection fraction ≤40% and were related to survival. Increased QTc was strongly related to mortality in the whole group and in subsets on the basis of age and the level of LV systolic dysfunction. There was a graded increase in mortality rate with an increase in QTc. The effect of QTc on mortality was incremental to the effects of age and ejection fraction. QT interval was measurable in ≥6 leads in 1193 patients in whom QTd was computed. QTd higher than the mean value of 35 ms was associated with an increase in all cause mortality (P = .04). Its mortality impact was most pronounced in the older patients, patients with more severe LV dysfunction, and patients with increased QTc.Conclusions Both QTc prolongation and increased QTd are associated with higher mortality rate in patients with moderate and severe LV dysfunction. (Am Heart J 2003;145:132-8.)     

Characterization of zebrafish full-length prothrombin cDNA and linkage group mapping

In this paper, we report the complete cDNA sequence of zebrafish prothrombin. The cDNA sequence predicts that zebrafish prothrombin is synthesized as a pre-proprotein consisting of a Gla domain, two kringle domains, and a two-chain protease domain. Zebrafish prothrombin is structurally very similar to human and other vertebrate prothrombins. Zebrafish and human prothrombin share 53% amino acid identity whereas zebrafish and hagfish prothrombin share 51% identity. Amino acid alignments of various prothrombins identified conservation of many of the functional/structural motifs suggesting that the vertebrate prothrombins may have similar functions. The three-dimensional structure of prothrombin predicted by homology modeling also revealed that the prothrombin fragment 1 and the catalytic domain structures are well conserved except for the insertion of an extra 7-amino-acid loop in the connecting region (CR) between the Gla and kringle I domain of fragment 1. Linkage analysis revealed that the prothrombin gene locus on linkage group 7 in zebrafish is syntenic to the human chromosome 11-prothrombin region suggesting its preservation through evolution. The availability of this cDNA sequence in zebrafish adds to our knowledge of the zebrafish hemostatic system and provides support for the view that similarities between zebrafish and mammalian coagulation exist, thus underscoring the relevance of the zebrafish model for studying human hemostasis.     

Ovarian follicular concentrations of activin, follistatin, inhibin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-2 (IGFBP-2), IGFBP-3, and vascular endothelial growth factor in spontaneous menstrual cycles of normal women of advanced reproductive age

Previous studies indicate that the menstrual cycles of older reproductive age women are characterized by a selective elevation of FSH associated with early development and ovulation of a dominant follicle. Several intraovarian hormones and growth factors have been identified that appear to serve important paracrine roles. The purpose of this study was to examine follicular fluid (FF) hormones and growth factors in the dominant follicle of unstimulated cycles of older, ovulatory women. We aspirated FF from the preovulatory dominant follicle in natural menstrual cycles of older subjects (age, 40-45 yr; n = 20) and younger controls (age, 20-25 yr; n = 19). FF was analyzed for estradiol, progesterone, testosterone, androstenedione, inhibin A and B, total activin A, total follistatin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-2 (IGFBP-2), IGFBP-3, and vascular endothelial growth factor (VEGF) concentrations. We found that the dominant follicles from older women contain normal concentrations of steroids, inhibin A and B, IGF-II, IGFBP-2, and IGFBP-3; increased concentrations of follistatin, activin A, and VEGF; and decreased concentrations of IGF-I. Therefore, under the influence of elevated FSH, the dominant follicle in older women is highly competent in terms of hormone and growth factor secretion. We postulate that elevated FF activin may be related to the early ovulation observed in older women, whereas elevated VEGF may be related to the meiotic spindle abnormalities observed in the oocytes of older reproductive age women.     

Recent Findings in the Genetics of Blood Pressure: How to Apply in Practice or Is a Moonshot Required?

Purpose of Review

Hypertension is recognised as the biggest contributor to the global burden of disease, but it is controlled in less than a fifth of patients worldwide, despite being relatively easy to detect and the availability of inexpensive safe generic drugs. Blood pressure is regulated by a complex network of physiologic pathways with currently available drugs targeting key receptors or enzymes in the top pathways. Major advances in the dissection of both monogenic and polygenic determinants of blood pressure regulation and variation have not resulted in rapid translation of these discoveries into clinical applications or precision medicine.

Recent Findings

Uromodulin is an example of a novel gene for hypertension identified from genome-wide association studies, currently the basis of a clinical trial to reposition loop diuretics in hypertension management. Gene-editing studies have established a genome-wide association studies (GWAS) SNP in chromosome 6p24, implicated in six conditions including hypertension, as a distal regulator of the endothelin-1 gene around 3000 base pairs away. Genomics of aldosterone-producing adenomas bring to focus the paradox in genomic medicine where availability of cheap generic drugs may render precision medicine uneconomical.

Summary

The speed of technology-driven genomic discoveries and the sluggish traditional pathways of drug development and translation need harmonisation to make a timely and early impact on global public health. This requires a directed collaborative effort for which we propose a hypertension moonshot to make a quantum leap in hypertension management and cardiovascular risk reduction by bringing together traditional bioscience, omics, engineering, digital technology and data science.