ß blockers switched to first-line therapy in hypertension.

In their recent guidelines, the European Society of Hypertension upgraded ß blockers, putting them on equal footing with thiazide diuretics, renin-angiotensin system blockers (eg, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and calcium channel blockers. The reason offered for upgrading ß blockers was the observation that they are often used for many other clinical conditions commonly encountered with hypertension. This upgrade would allow for the treatment of two conditions with a single drug (a so-called twofer). In most current national and international hypertension guidelines, ß blockers are only considered to be an alternative when there are specific indications. Compared with the other first-line antihypertensive drug classes, ß blockers are significantly less effective in preventing stroke and cardiovascular mortality. To relegate ß blockers to an inferiority status as previous guidelines have done was based on the evidence in aggregate, and still stands. No new evidence supports the switch of ß blockers back to first-line therapy. We are concerned that this move might lead to widespread harm because of inferior stroke protection.

Potassium intake: the Cinderella electrolyte.

Dietary guidelines recommend intake targets for some essential minerals, based on observational and experimental evidence relating mineral intake levels to health outcomes. For prevention of cardiovascular disease, reducing sodium intake and increasing potassium intake are the principal tools. While reducing sodium intake has received greatest public health priority, emerging evidence suggests that increasing potassium intake may be a more important target for cardiovascular prevention. Increased potassium intake reduces blood pressure and mitigates the hypertensive effects of excess sodium intake, and the recent large Phase III SSaSS trial reported that increasing potassium intake (and reducing sodium intake) in populations with low potassium intake and high sodium intake, through salt substitution (25% KCl, 75%NaCl), reduces the risk of stroke in patients at increased cardiovascular risk. As key sources of potassium intake include fruit, vegetables, nuts, and legumes, higher potassium intake may be associated with healthy dietary patterns. The current review makes the case that increasing potassium intake might represent a more advantageous dietary strategy for prevention of cardiovascular disease. Future research should focus on addressing the independent effect of potassium supplementation in populations with low or moderate potassium intake, and determine effective strategies to increase potassium intake from diet.

Age-Related Macular Degeneration and Mitochondria-Associated Autoantibodies: A Review of the Specific Pathogenesis and Therapeutic Strategies.

Age-related macular degeneration (AMD) is a severe retinal disease that causes irreversible visual loss and blindness in elderly populations worldwide. The pathological mechanism of AMD is complex, involving the interactions of multiple environmental and genetic factors. A poor understanding of the disease leads to limited treatment options and few effective prevention methods. The discovery of autoantibodies in AMD patients provides an opportunity to explore the pathogenesis and treatment direction of the disease. This review focuses on the mitochondria-associated autoantibodies and summarizes the functional roles of mitochondria under physiological conditions and their alterations during the pathological states. Additionally, it discusses the crosstalk between mitochondria and other organelles, as well as the mitochondria-related therapeutic strategies in AMD.

Association of autoantibody levels with different stages of age-related macular degeneration (AMD): Results from the population-based Gutenberg Health Study (GHS).

PURPOSE: Anti-retinal autoantibodies are assumed to be associated with age-related macular degeneration (AMD). To our knowledge, this is the first evaluation of autoantibodies in human sera of participants with different stages of AMD in a large population-based, observational cohort study in Germany. METHODS: The Gutenberg Health Study (GHS) is a population-based, observational cohort study in Germany, including 15,010 participants aged between 35 and 74. Amongst others, non-mydriatic fundus photography (Visucam PRO NM™, Carl Zeiss Meditec AG, Jena, Germany) was performed. Fundus images of the first 5000 participants were graded based on the Rotterdam Eye Study classification. Sera of participants with AMD (n=541) and sera of age-matched participants without AMD (n=490) were analyzed by antigen-microarrays. Besides descriptive statistics, autoantibody-levels were compared by Mann-Whitney-U test and the associations of level of autoantibodies with AMD were calculated by logistic regression analysis. Likewise, possible associations of the autoantibodies and both clinical and laboratory parameters on AMD subjects were analyzed. RESULTS: Autoantibodies against transferrin (p<0.001) were significantly downregulated in participants with early AMD and soft, distinct drusen (≥63 µm) or pigmentary abnormalities only compared to Controls. Mitogen-activated protein kinase 3 (p=0.041), glutathione peroxidase 4 (p=0.048), clusterin (p=0.045), lysozyme (p=0.19), protein kinase C substrate 80K-H (p=0.02), heat shock 70 kDa protein 1A (p=0.04) and insulin (p=0.018) show a trend between Control and participants with early AMD and soft, distinct drusen (≥63 µm) or pigmentary abnormalities only. CONCLUSIONS: This study contributes to a growing knowledge of autoantibodies in association with different AMD stages compared to controls in the context of a large population-based study in Germany. Especially autoantibodies against inflammatory proteins were downregulated in participants with early AMD and soft, distinct drusen (≥63 µm) or pigmentary abnormalities only.

What is resistant arterial hypertension?

PURPOSE: The current review is to describe the definition and prevalence of resistant arterial hypertension (RAH), the difference between refractory hypertension, patient characteristics and major risk factors for RAH, how RAH is diagnosed, prognosis and outcomes for patients. MATERIALS AND METHODS: According to the WHO, approximately 1.28 billion adults aged 30-79 worldwide have arterial hypertension, and over 80% of them do not have blood pressure (BP) under control. RAH is defined as above-goal elevated BP despite the concurrent use of 3 or more classes of antihypertensive drugs, commonly including a long-acting calcium channel blocker, an inhibitor of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a thiazide diuretic administered at maximum or maximally tolerated doses and at appropriate dosing frequency. RAH occurs in nearly 1 of 6 hypertensive patients. It often remains unrecognised mainly because patients are not prescribed ≥3 drugs at maximal doses despite uncontrolled BP. CONCLUSION: RAH distinctly increases the risk of developing coronary artery disease, heart failure, stroke and chronic kidney disease and confers higher rates of major adverse cardiovascular events as well as increased all-cause mortality. Timely diagnosis and treatment of RAH may mitigate the associated risks and improve short and long-term prognosis.

Resistant arterial hypertension is a serious condition that leads to severe cardiovascular complications, such as heart attack, stroke and death.It is defined as above-goal elevated blood pressure despite the concurrent use of 3 or more classes of antihypertensive medications administered at maximum or maximally tolerated doses and at appropriate dosing frequency.Non-adherence to antihypertensive medications must be excluded before resistant arterial hypertension is diagnosed.Blood pressure should be measured appropriately. A person should sit in a comfortable chair with back supported, both feet flat on the ground, and legs uncrossed for at least 5 min before blood pressure measurement. A cuff length is supposed to be at least 80% and a width of at least 40% of the arm circumference. Placing the cuff directly on the skin of the upper arm at the level of the heart. Obtaining 3 readings 1 min apart. Discarding the first reading and taking the mean of the second and third readingsResistant arterial hypertension should be distinguished from refractory hypertension, when blood pressure remains uncontrolled on maximal or near-maximal therapy of 5 or more antihypertensive agents of different classes.

Lectin-Based Affinity Enrichment and Characterization of N-Glycoproteins from Human Tear Film by Mass Spectrometry.

The glycosylation of proteins is one of the most common post-translational modifications (PTMs) and plays important regulatory functions in diverse biological processes such as protein stability or cell signaling. Accordingly, glycoproteins are also a consistent part of the human tear film proteome, maintaining the proper function of the ocular surface and forming the first defense barrier of the ocular immune system. Irregularities in the glycoproteomic composition of tear film might promote the development of chronic eye diseases, indicating glycoproteins as a valuable source for biomarker discovery or drug target identification. Therefore, the present study aimed to develop a lectin-based affinity method for the enrichment and concentration of tear glycoproteins/glycopeptides and to characterize their specific N-glycosylation sites by high-resolution mass spectrometry (MS). For method development and evaluation, we first accumulated native glycoproteins from human tear sample pools and assessed the enrichment efficiency of different lectin column systems by 1D gel electrophoresis and specific protein stainings (Coomassie and glycoproteins). The best-performing multi-lectin column system (comprising the four lectins ConA, JAC, WGA, and UEA I, termed 4L) was applied to glycopeptide enrichment from human tear sample digests, followed by MS-based detection and localization of their specific N-glycosylation sites. As the main result, our study identified a total of 26 N glycosylation sites of 11 N-glycoproteins in the tear sample pools of healthy individuals (n = 3 biological sample pools). Amongst others, we identified tear film proteins lactotransferrin (N497 and N642, LTF), Ig heavy chain constant α-1 (N144 and 340, IGHA1), prolactin-inducible protein (N105, PIP), and extracellular lacritin (N105, LACRT) as highly reliable and significant N glycoproteins, already associated with the pathogenesis of various chronic eye diseases such as dry eye syndrome (DES). In conclusion, the results of the present study will serve as an important tear film N-glycoprotein catalog for future studies focusing on human tear film and ocular surface-related inflammatory diseases.

Chlorthalidone vs Hydrochlorothiazide for Hypertension-CV Events: Did the Design Influence the Outcome?

The Diuretic Comparison Project (DCP)1 was a real world study planned to evaluate in a pragmatic manner whether Chlorthalidone (CTD), as compared with Hydrochlorothiazide (HCTZ), would reduce the risk of major nonfatal cardiovascular disease outcomes in elderly hypertensive participants (≥65 years) who were receiving HCTZ (25 or 50 mg) at baseline. This study being a real world study lacks the robustness of a randomized controlled trial. The principle limitation being unequal exposure of the two diuretics, prolonged unknown duration of exposure to HCTZ vs a short exposure to CTD (Median 2.4 years). In the high risk population with history of MI/Stroke, CTD conferred a lower risk of primary outcome as compared to low risk population where no significant difference in outcome was seen in both diuretics. Other factors included, lack of established dose equivalency of the two diuretics and absence of use of 12.5 mg HCTZ in older hypertensives. How to cite this article: Pareek A, Messerli FH, Ram CVS. Chlorthalidone vs Hydrochlorothiazide for Hypertension-CV Events: Did the Design Influence the Outcome? J Assoc Physicians India 2023;71(10):93-93.

Sodium intake, life expectancy, and all-cause mortality.

AIMS: Since dietary sodium intake has been identified as a risk factor for cardiovascular disease and premature death, a high sodium intake can be expected to curtail life span. We tested this hypothesis by analysing the relationship between sodium intake and life expectancy as well as survival in 181 countries worldwide. METHODS AND RESULTS: We correlated age-standardized estimates of country-specific average sodium consumption with healthy life expectancy at birth and at age of 60 years, death due to non-communicable diseases and all-cause mortality for the year of 2010, after adjusting for potential confounders such as gross domestic product per capita and body mass index. We considered global health estimates as provided by World Health Organization. Among the 181 countries included in this analysis, we found a positive correlation between sodium intake and healthy life expectancy at birth (ß = 2.6 years/g of daily sodium intake, R2 = 0.66, P < 0.001), as well as healthy life expectancy at age 60 (ß = 0.3 years/g of daily sodium intake, R2 = 0.60, P = 0.048) but not for death due to non-communicable diseases (ß = 17 events/g of daily sodium intake, R2 = 0.43, P = 0.100). Conversely, all-cause mortality correlated inversely with sodium intake (ß = -131 events/g of daily sodium intake, R2 = 0.60, P < 0.001). In a sensitivity analysis restricted to 46 countries in the highest income class, sodium intake continued to correlate positively with healthy life expectancy at birth (ß = 3.4 years/g of daily sodium intake, R2 = 0.53, P < 0.001) and inversely with all-cause mortality (ß = -168 events/g of daily sodium intake, R2 = 0.50, P < 0.001). CONCLUSION: Our observation of sodium intake correlating positively with life expectancy and inversely with all-cause mortality worldwide and in high-income countries argues against dietary sodium intake being a culprit of curtailing life span or a risk factor for premature death. These data are observational and should not be used as a base for nutritional interventions.

Dynamin-like Protein 1 (DNML1) as a Molecular Target for Antibody-Based Immunotherapy to Treat Glaucoma.

Slow and progressive loss of retinal ganglion cells (RGCs) is the main characteristic of glaucoma, the second leading cause of blindness worldwide. Previous studies have shown that impaired mitochondrial dynamics could facilitate retinal neurodegeneration. Mitochondrial dynamics are regulated directly (fission) or more indirectly (fusion) by dynamin-like protein 1 (DNML1). Therefore, DNM1L might be a promising target for an antibody-based approach to treat glaucoma. The consequences of targeting endogenous DNM1L by antibodies in a glaucoma animal model have not been investigated yet. Here, we show that the intravitreal application of an anti-DNM1L antibody showed protective effects regarding the survival of RGCs and their axons in the retinal nerve fiber layer (RNFL). Antibody treatment also improved retinal functionality, as observed by electroretinography (Ganzfeld ERG). Western blot analysis revealed altered DNM1L phosphorylation and altered expression of proteins related to apoptosis suggesting a decreased apoptosis rate. Mass spectrometry analysis revealed 28 up-regulated and 21 down-regulated proteins (p < 0.05) in both experimental groups. Protein pathway analysis showed that many proteins interacted directly with the target protein DNM1L and could be classified into three main protein clusters: Vesicle traffic-associated (NSF, SNCA, ARF1), mitochondrion-associated (HSP9A, SLC25A5/ANT2, GLUD1) and cytoskeleton-associated (MAP1A) signaling pathway. Our results demonstrate that DNM1L is a promising target for an antibody-based approach to glaucoma therapy.

A Monoclonal Anti-HMGB1 Antibody Attenuates Neurodegeneration in an Experimental Animal Model of Glaucoma.

Neuroinflammation is a crucial process for the loss of retinal ganglion cells (RGC), a major characteristic of glaucoma. High expression of high-mobility group box protein 1 (HMGB1) plays a detrimental role in inflammatory processes and is elevated in the retinas of glaucoma patients. Therefore, this study aimed to investigate the effects of the intravitreal injection of an anti-HMGB1 monoclonal antibody (anti-HMGB1 Ab) in an experimental animal model of glaucoma. Two groups of Spraque Dawley rats received episcleral vein occlusion to chronically elevate intraocular pressure (IOP): (1) the IgG group, intravitreal injection of an unspecific IgG as a control, n = 5, and (2) the HMGB1 group, intravitreal injection of an anti-HMGB1 Ab, n = 6. IOP, retinal nerve fiber layer thickness (RNFLT), and the retinal flash response were monitored longitudinally. Post-mortem examinations included immunohistochemistry, microarray, and mass spectrometric analysis. RNFLT was significantly increased in the HMGB1 group compared with the IgG group (p < 0.001). RGC density showed improved neuronal cell survival in the retina in HMGB1 compared with the IgG group (p < 0.01). Mass spectrometric proteomic analysis of retinal tissue showed an increased abundance of RNA metabolism-associated heterogeneous nuclear ribonucleoproteins (hnRNPs), such as hnRNP U, D, and H2, in animals injected with the anti-HMGB1 Ab, indicating that the application of the antibody may cause increased gene expression. Microarray analysis showed a significantly decreased expression of C-X-C motif chemokine ligand 8 (CXCL8, p < 0.05) and connective tissue growth factor (CTGF, p < 0.01) in the HMGB1 group. Thus, these data suggest that intravitreal injection of anti-HMGB1 Ab reduced HMGB1-dependent inflammatory signaling and mediated RGC neuroprotection.

Increased Arterial Responsiveness to Angiotensin II in Mice Conceived by Assisted Reproductive Technologies.

Since the first report in 1978, the number of individuals conceived by Assisted Reproductive Technologies (ART) has grown incessantly. In parallel, with the recent emergence of possible underlying mechanisms of ART-induced epigenetic changes in the renin-angiotensin system, the cardiovascular repercussions of ART in mice and human offspring (including arterial hypertension, vascular dysfunction, and cardiac remodeling) have become increasingly recognized. Here, we hypothesized that ART may increase arterial responsiveness to angiotensin II (ANG II) by epigenetically modifying the expression of its receptors. To test this hypothesis, we assessed the vasoconstrictor responsiveness to ANG II in isolated aortas from ART and control mice. We also examined ANG II receptor (ATR) type 1 and 2 expression and the promoter methylation of the At1aR, At1bR and At2R genes. We found that the vasoconstrictor response to ANG II was markedly increased in ART mice compared to controls. This exaggerated vasoconstrictor responsiveness in ART mice correlated with a significant increase in the ANG II receptor (ATR) type 1 to ATR type 2 protein expression ratio in the aorta; this was mainly driven by an increase in AT1R expression, and by hypomethylation of two CpG sites located in the At1bR gene promoter leading to increased transcription of the gene. We conclude that in mice, ART increase the vasoconstrictor response to ANG II in the aorta by epigenetically causing an imbalance between the expression of vasoconstrictor (AT1R) and vasodilator (AT2R) ANG II receptors. Unbalanced expression of AT1R and AT2R receptors seems to be a novel mechanism contributing to ART-induced arterial hypertension in mice.

Tear Film-specific Biomarkers in Glaucoma Patients. / Tränenfilmspezifische Biomarker bei Glaukompatienten.

Glaucoma is a group of chronic eye diseases that lead to degeneration of retinal ganglion cells (RGCs) and their axons followed by irreversible loss of vision in the patient. Glaucoma is a disease that initially evolves asymptomatically with the first symptoms appearing only at an advanced stage of this eye disease. For this reason, it is always necessary to develop state-of-the-art technologies and methods for the identification and characterization of new, specific biomarkers for the early diagnosis of glaucoma. Therefore, the analysis of biological fluids, as in this case the tear fluid of patients, represents an attractive source to identify new specific as well as sensitive biomarkers in glaucoma. These biomarkers could be involved in the pathophysiological processes of glaucoma or possibly serve for diagnostic differentiation of various types of glaucoma.

Soluble fms-like tyrosine kinase 1 (sFlt-1): A novel biochemical marker for acute fatty liver of pregnancy.

INTRODUCTION: Acute fatty liver of pregnancy (AFLP) substantially contributes to maternal and neonatal morbidity and mortality. Other liver-associated pregnancy complications such as preeclampsia-associated HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome may be difficult to differentiate from AFLP as these diseases overlap with regard to multiple clinical and laboratory features. The aim of this study was to investigate angiogenic profiles by measuring soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in pregnancies compromised by AFLP and to compare them with those complicated by HELLP syndrome. MATERIAL AND METHODS: Pregnant women affected by AFLP or HELLP syndrome were enrolled. The study population of women with HELLP syndrome was part of a larger data collection obtained in our clinic that has been used for previous work. Patients' angiogenic profiles were assessed by measuring sFlt-1 and PlGF serum levels. To assess the diagnostic potential of these angiogenic markers in AFLP, as well as discriminating it from HELLP syndrome, non-parametric tests were used and receiver operating curves were calculated. RESULTS: Six women with AFLP and 48 women with HELLP syndrome were included in the study. Patients with AFLP showed significantly higher sFlt-1 levels (median: 57 570 pg/mL; range 31 609-147 170 pg/mL) than patients with HELLP syndrome (9713 pg/mL; 1348-30 781 pg/mL; p < 0.001). PlGF serum levels were higher in patients with AFLP compared with those with HELLP syndrome (197 pg/mL; 127-487 pg/mL vs. 40 pg/mL; 9-644 pg/mL, respectively; p < 0.01). sFlt-1/PlGF ratios were not significantly different between AFLP and HELLP syndrome patients (192; 157-1159 vs. 232; 3-948, respectively; NS). In our study population, an sFlt-1 cut-off value of 31 100 pg/mL allowed differentiation between these two diseases with a sensitivity and specificity of 100%. A linear correlation was found between the cumulative numbers of Swansea criteria and sFlt-1 serum levels (r = 0.97; p < 0.01). CONCLUSIONS: AFLP is associated with very high sFlt-1 serum levels in particular in women fulfilling eight or more Swansea criteria. Besides the suggested Swansea criteria to diagnose AFLP, an sFlt-1 value above 31 100 pg/mL may be an additional biochemical feature improving discrimination between AFLP and HELLP syndrome. However, because of the small number of pregnancies affected by AFLP included in this work further studies are needed to corroborate our findings.

Salt and cardiovascular disease: insufficient evidence to recommend low sodium intake.

Several blood pressure guidelines recommend low sodium intake (<2.3 g/day, 100 mmol, 5.8 g/day of salt) for the entire population, on the premise that reductions in sodium intake, irrespective of the levels, will lower blood pressure, and, in turn, reduce cardiovascular disease occurrence. These guidelines have been developed without effective interventions to achieve sustained low sodium intake in free-living individuals, without a feasible method to estimate sodium intake reliably in individuals, and without high-quality evidence that low sodium intake reduces cardiovascular events (compared with moderate intake). In this review, we examine whether the recommendation for low sodium intake, reached by current guideline panels, is supported by robust evidence. Our review provides a counterpoint to the current recommendation for low sodium intake and suggests that a specific low sodium intake target (e.g. <2.3 g/day) for individuals may be unfeasible, of uncertain effect on other dietary factors and of unproven effectiveness in reducing cardiovascular disease. We contend that current evidence, despite methodological limitations, suggests that most of the world's population consume a moderate range of dietary sodium (2.3-4.6g/day; 1-2 teaspoons of salt) that is not associated with increased cardiovascular risk, and that the risk of cardiovascular disease increases when sodium intakes exceed 5 g/day. While current evidence has limitations, and there are differences of opinion in interpretation of existing evidence, it is reasonable, based upon observational studies, to suggest a population-level mean target of <5 g/day in populations with mean sodium intake of >5 g/day, while awaiting the results of large randomized controlled trials of sodium reduction on incidence of cardiovascular events and mortality.

An Analysis of Online Ratings of Pediatric Orthopaedic Surgeons.

BACKGROUND: Patients continue to utilize physician review websites (PRWs) to assist in their selection of a health care provider. Studies on PRWs and how they affect patient care have recently become popular in the literature. This study analyzes PRW ratings of a previously unexamined subspecialty, pediatric orthopaedic surgeons. METHODS: Three hundred ninety-nine randomly selected Pediatric Orthopaedic Society of North America member's PRW ratings were examined from May 4, 2020 to July 18, 2020. Healthgrades.com, Vitals.com, RateMDs.com, and Google.com were reviewed. Number of ratings and average ratings (0 to 5.0) were recorded. Provider sex, years in practice (0 to 10, 11 to 20, and 21+), practice type (academic, private), geographic location (Northeast, Southeast, Midwest, Southwest, West), degree (Medical Doctor, Doctor of Osteopathic Medicine), and fellowship training (yes, no) were recorded. Kruskal-Wallis testing was performed to determine factors affecting positive surgeon ratings. RESULTS: 98.5% (393) of Pediatric Orthopaedic Society of North America surgeons were rated on a PRW at least once and were highly rated with an average rating of 4.14 of 5.0. Surgeons in practice 1 to 10 years had higher ratings than those in practice 11 to 20 and 21+ years, on Healthgrades.com (P=0.049) and RateMDs.com (P=0.011). Academic surgeons were found to have higher ratings than those in private practice on Google.com (P=0.007). Sex, region of practice, degree type, and fellowship training status did not have an effect on online ratings across all PRWs. CONCLUSIONS: Pediatric orthopaedic surgeons are frequently and highly rated, similar to other orthopaedic subspecialties. Surgeons in practice 1 to 10 years were found to have statistically higher ratings on some websites. Academic surgeons were found to have statistically higher ratings on some websites.

Contribution of the Commensal Microflora to the Immunological Homeostasis and the Importance of Immune-Related Drug Development for Clinical Applications.

Not long ago, self-reactive immune activity was considered as pathological trait. A paradigm shift has now led to the recognition of autoimmune processes as part of natural maintenance of molecular homeostasis. The immune system is assigned further roles beneath the defense against pathogenic organisms. Regarding the humoral immune system, the investigation of natural autoantibodies that are frequently found in healthy individuals has led to further hypotheses involving natural autoimmunity in other processes as the clearing of cellular debris or decrease in inflammatory processes. However, their role and origin have not been entirely clarified, but accumulating evidence links their formation to immune reactions against the gut microbiome. Antibodies targeting highly conserved proteins of the commensal microflora are suggested to show self-reactive properties, following the paradigm of the molecular mimicry. Here, we discuss recent findings, which demonstrate potential links of the commensal microflora to the immunological homeostasis and highlight the possible implications for various diseases. Furthermore, specific components of the immune system, especially antibodies, have become a focus of attention for the medical management of various diseases and provide attractive treatment options in the future. Nevertheless, the development and optimization of such macromolecules still represents a very time-consuming task, shifting the need to more medical agents with simple structural properties and low manufacturing costs. Synthesizing only the biologically active sites of antibodies has become of great interest for the pharmaceutical industry and offers a wide range of therapeutic application areas as it will be discussed in the present review article.

Body-Weight Fluctuations and Outcomes in Coronary Disease.

BACKGROUND: Body-weight fluctuation is a risk factor for death and coronary events in patients without cardiovascular disease. It is not known whether variability in body weight affects outcomes in patients with coronary artery disease. METHODS: We determined intraindividual fluctuations in body weight from baseline weight and follow-up visits and performed a post hoc analysis of the Treating to New Targets trial, which involved assessment of the efficacy and safety of lowering low-density lipoprotein cholesterol levels with atorvastatin. The primary outcome was any coronary event (a composite of death from coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, revascularization, or angina). Secondary outcomes were any cardiovascular event (a composite of any coronary event, a cerebrovascular event, peripheral vascular disease, or heart failure), death, myocardial infarction, or stroke. RESULTS: Among 9509 participants, after adjustment for risk factors, baseline lipid levels, mean body weight, and weight change, each increase of 1 SD in body-weight variability (measured according to average successive variability and used as a time-dependent covariate) was associated with an increase in the risk of any coronary event (2091 events; hazard ratio, 1.04; 95% confidence interval [CI], 1.01 to 1.07; P=0.01), any cardiovascular event (2727 events; hazard ratio, 1.04; 95% CI, 1.02 to 1.07; P<0.001), and death (487 events; hazard ratio,1.09; 95% CI, 1.07 to 1.12; P<0.001). Among patients in the quintile with the highest variation in body weight, the risk of a coronary event was 64% higher, the risk of a cardiovascular event 85% higher, death 124% higher, myocardial infarction 117% higher, and stroke 136% higher than it was among those in the quintile with the lowest variation in body weight in adjusted models. CONCLUSIONS: Among participants with coronary artery disease, fluctuation in body weight was associated with higher mortality and a higher rate of cardiovascular events independent of traditional cardiovascular risk factors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00327691 .).

Minocycline reduces inflammatory response and cell death in a S100B retina degeneration model.

BACKGROUND: Previous studies noted that intravitreal injection of S100B triggered a glaucoma-like degeneration of retina and optic nerve as well as microglia activation after 14 days. The precise role of microglia in our intravitreal S100B model is still unclear. Hence, microglia were inhibited through minocycline. The aim is to investigate whether microglia have a significant influence on the degeneration process or whether they are only a side effect in the model studied here. METHODS: Minocycline was applied daily in rats by intraperitoneal injection using two different concentrations (13.5 mg/kg body weight, 25 mg/kg body weight). One day after treatment start, S100B or PBS was intravitreally injected in one eye per rat. The naïve groups received no injections. This resulted in a total of five groups (naïve n = 14, PBS n = 14, S100B n = 13, 13.5 mg/kg mino n = 15, 25 mg/kg mino n = 15). At day 14, electroretinogram measurements were performed, followed by immunofluorescence and label-free quantitative proteomics analysis. The focus of these investigations was on the survival of RGCs as well as their axons, the response of the microglia, and the identification of further pathological modes of action of S100B. RESULTS: The best signal transmission was detected via ERG in the 13.5 mg/kg mino group. The inhibition of the microglia protected optic nerve neurofilaments and decreased the negative impact of S100B on RGCs. However, the minocycline treatment could not trigger complete protection of RGCs. Furthermore, in retina and optic nerve, the minocycline treatment reduced the number and activity of S100B-triggered microglia in a concentration-dependent manner. Proteomics analysis showed that S100B application led to numerous metabolic functions and cellular stress, mainly an increased inflammatory response, glycolysis, and mitochondrial dysfunction, which caused oxidative stress in the retina. Importantly, the protective capability of lower dose of minocycline was unraveled by suppressing the apoptotic, inflammatory, and the altered metabolic processes caused by S100B insult in the retina. CONCLUSION: Intravitreally injected S100B not only led to a pro-inflammatory microglial reaction, but also a mitochondrial and metabolic dysfunction. Also, these results suggest that an excessive microglial response may be a significant degenerative factor, but not the only trigger for increased cell death.

An Analysis of Online Ratings of Hip and Knee Surgeons.

BACKGROUND: Public domain physician review websites (PRWs) and personal websites are extremely popular measures that patients use to evaluate physicians before receiving care. Few studies have examined how orthopedic surgeons are rated on PRWs and personal websites. This study examines the online ratings of hip and knee replacement subspecialists. METHODS: The American Association of Hip and Knee Surgeons (AAHKS) fellow's ratings were examined from October 1st, 2018 to December 31st, 2018, on Healthgrades.com, Vitals.com, RateMDs.com, Google.com, and personal websites. Number of responses and average ratings (0.0-5.0) were recorded, along with provider gender, years in practice (0-10, 11-20, and 21+), practice type (academic, private), geographic region (NE, SE, MW, SW, W), degree (MD, DO), and fellowship training (yes, no). The Kruskal-Wallis testing was performed to determine factors affecting positive surgeon ratings. RESULTS: 98.3% (483) of 490 AAHKS surgeons were rated at least once. No significant differences in average ratings were identified between websites. Surgeons in practice 1-10 years had significantly higher ratings than those in practice 11-20 and 21+ years (P < .01). Fellowship-trained surgeons in practice 1-10 years also showed significantly higher ratings. No differences in average ratings were found between gender, practice type, and geographic region. CONCLUSIONS: AAHKS surgeons have high average ratings and are rated online frequently. Surgeons in practice 1-10 years had statistically higher overall average ratings. Adult reconstruction fellowship training was also associated with higher average ratings for surgeons in practice 1-10 years. Public domain PRWs and personal websites showed no difference in average ratings.