Although fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a focused manner. The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community. This nonclassical heating technique is slowly moving from a laboratory curiosity to an established technique that is heavily used in both academia and industry. The efficiency of "microwave flash heating" in dramatically reducing reaction times (from days and hours to minutes and seconds) is just one of the many advantages. This Review highlights recent applications of controlled microwave heating in modern organic synthesis, and discusses some of the underlying phenomena and issues involved.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200400655

Controlled microwave heating in modern organic synthesis.

There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

Why most published research findings are false

The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjogren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.

TFOS DEWS II pathophysiology report

The tarsal glands of Meibom (glandulae tarsales) are large sebaceous glands located in the eyelids and, unlike those of the skin, are unassociated with hairs. According to Duke-Elder and Wyler,1 they were first mentioned by Galenus in 200 AD and later, in 1666, they were described in more detail by the German physician and anatomist Heinrich Meibom, after whom they are named.

Lipids produced by the meibomian glands are the main component of the superficial lipid layer of the tear film that protects it against evaporation of the aqueous phase and is believed also to stabilize the tear film by lowering surface tension.2 Hence, meibomian lipids are essential for the maintenance of ocular surface health and integrity.

Although they share certain principal characteristics with ordinary sebaceous glands, they have several distinct differences in anatomy, location, secretory regulation, composition of their secretory product, and function.

Functional disorders of the meibomian glands, referred to today as meibomian gland dysfunction (MGD),3 are increasingly recognized as a discrete disease entity.4–8 In patients with dry eye disease, alterations in the lipid phase that point to MGD are reportedly more frequent than isolated alterations in the aqueous phase. In a study by Heiligenhaus et al.,9 a lipid deficiency occurred in 76.7% of dry eye patients compared with only 11.1% of those with isolated alterations of the aqueous phase. This result is in line with the observations by Shimazaki et al.10 of a prevalence of MGD in the absolute majority of eyes with ocular discomfort defined as dry eye symptoms. These observations noted that 64.6% of all such eyes and 74.5% of those excluding a deficiency of aqueous tear secretion were found to have obstructive MGD, or a loss of glandular tissue, or both.10 Horwath-Winter et al.11 reported MGD in 78% of dry eye patients or, if only non-Sjogren patients are considered, in 87% compared with 13% with isolated aqueous tear deficiency. It may thus be accepted that MGD is important, conceivably underestimated, and possibly the most frequent cause of dry eye disease due to increased evaporation of the aqueous tears.5,9–12

After some excellent reviews of MGD4,7,8,13,14 in the past, many new findings have been reported in recent years, and other questions remain to be identified and resolved. A sound understanding of meibomian gland structure and function and its role in the functional anatomy of the ocular surface15 is needed, to understand the contribution of the meibomian glands to dysfunction and disease. Herein, we seek to provide a comprehensive review of physiological and pathophysiological aspects of the meibomian glands.

/pdf/the-international-workshop-on-meibomian-gland-dysfunction-1rohh1kg6i.pdf

The International Workshop on Meibomian Gland Dysfunction: Report of the Subcommittee on Anatomy, Physiology, and Pathophysiology of the Meibomian Gland

The members of the Management and Therapy Subcommittee undertook an evidence-based review of current dry eye therapies and management options. Management options reviewed in detail included treatments for tear insufficiency and lid abnormalities, as well as anti-inflammatory medications, surgical approaches, dietary modifications, environmental considerations and complementary therapies. Following this extensive review it became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size. Reflecting on all available evidence, a staged management algorithm was derived that presents a step-wise approach to implementing the various management and therapeutic options according to disease severity. While this exercise indicated that differentiating between aqueous-deficient and evaporative dry eye disease was critical in selecting the most appropriate management strategy, it also highlighted challenges, based on the limited evidence currently available, in predicting relative benefits of specific management options, in managing the two dry eye disease subtypes. Further evidence is required to support the introduction, and continued use, of many of the treatment options currently available to manage dry eye disease, as well as to inform appropriate treatment starting points and understand treatment specificity in relation to dry eye disease subtype.

TFOS DEWS II Management and Therapy Report

Objective: To assess subjective symptoms, tear func- tion factors, and ocular surface morphology in the clinical course of patients with dry eye syndrome under treatment within an observation period of up to 8 years. Methods: In 97 patients (78 women and 19 men) with ocular discomfort, a clinical diagnosis of dry eye syn- drome was made based on typical symptoms and a re- ducedtearfilmbreakuptimeoflessthan10seconds.Sub- sequent evaluations revealed a diagnosis of aqueous tear deficiency in 9 patients, meibomian gland dysfunction in32patients,andaqueousteardeficiencycombinedwith meibomianglanddysfunctionin30patients,aqueoustear deficiency associated with Sjogren syndrome in 12 pa- tients,andaqueousteardeficiencyandmeibomiangland dysfunction associated with Sjogren syndrome in 14 pa- tients. Follow-up assessments were performed 12 to 94 months (mean follow-up, 40 months) after the initial di- agnosis. Main Outcome Measures: In different subgroups of dry eye tear film breakup time, Schirmer test with- out local anesthesia (Schirmer I), fluorescein and rose bengal staining, impression cytology, as well as subjec- tive dry eye symptoms and frequency of tear substitute application were compared at baseline and after a fol- low-up of 1 to 8 years (mean, 3.3 years). Results: At baseline, tear film function and ocular sur- facetestresultsfoundmorepathologicabnormalitiesand more severe subjective symptoms in patients with aque- ousteardeficiencyassociatedwithSjogrensyndromeand aqueous tear deficiency and meibomian gland dysfunc- tion associated with Sjogren syndrome compared with the other groups who had dry eye syndrome. No differ- encesinfrequencyoftearsubstituteapplicationwereob- served. At follow-up, tear breakup time, Schirmer I test results, and corneal fluorescein staining improved com- pared with baseline values, whereas rose bengal stain- ing and impression cytology of the conjunctival surface remained almost unchanged. Subjective symptoms and frequency of artificial tear application were reduced.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/415735/ecs20250.pdf

Evaluation of the Clinical Course of Dry Eye Syndrome

There is strong and consistent evidence that oxidative stress is crucially involved in the development of atherosclerotic vascular disease. Overproduction of reactive oxygen species (ROS) in mitochondria is an unifying mechanism that underlies micro- and macrovascular atherosclerotic disease. Given the central role of mitochondria in energy and ROS production, mitochondrial DNA (mtDNA) is an obvious candidate for genetic susceptibility studies on atherosclerotic processes. We therefore examined the association between mtDNA haplogroups and coronary artery disease (CAD) as well as diabetic retinopathy. This study of Middle European Caucasians included patients with angiographically documented CAD (n = 487), subjects with type 2 diabetes mellitus with (n = 149) or without (n = 78) diabetic retinopathy and control subjects without clinical manifestations of atherosclerotic disease (n = 1527). MtDNA haplotyping was performed using multiplex PCR and subsequent multiplex primer extension analysis for determination of the major European haplogroups. Haplogroup frequencies of patients were compared to those of control subjects without clinical manifestations of atherosclerotic disease. Haplogroup T was significantly more prevalent among patients with CAD than among control subjects (14.8% vs 8.3%; p = 0.002). In patients with type 2 diabetes, the presence of diabetic retinopathy was also significantly associated with a higher prevalence of haplogroup T (12.1% vs 5.1%; p = 0.046). Our data indicate that the mtDNA haplogroup T is associated with CAD and diabetic retinopathy in Middle European Caucasian populations.

/pdf/mitochondrial-dna-haplogroup-t-is-associated-with-coronary-35bmm4us1e.pdf

Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study

Association of complement factor H Y402H gene polymorphism with different subtypes of exudative age-related macular degeneration.

Background: Many patients with essential blepharospasm also show dry eye signs and symptoms. Botulinum toxin A is an effective treatment for reducing spasms in these patients. In this investigation, the effect of botulinum toxin A injections on tear function and on the morphology of the ocular surface in patients suffering from blepharospasm in combination with a dry eye syndrome was investigated.

Methods: Botulinum toxin A injections were applied to 16 patients with blepharospasm. All patients complained of dry eye symptoms and had reduced tear break up time values. A subjective questionnaire and ocular examinations including tear break up time, Schirmer test without local anaesthesia, and rose bengal staining were evaluated before, 1 week, 1 month, and 3 months after injection. Impression cytology was performed before, 1 month, and 3 months after botulinum toxin A treatment.

Results: Although all patients were relieved of blepharospasm after botulinum toxin injections, only three noticed an improvement in dry eye symptoms. Eight patients noticed no difference and five complained of worsening. Tear break up time was found to be increased 1 week and 1 month after injections. Schirmer test measurements were reduced up to 3 months. Rose bengal staining slightly increased 1 week after injections. Impression cytology showed no definite change in conjunctival cell morphology 1 month and 3 months after botulinum toxin A injections.

Conclusion: In the patients presented here suffering from blepharospasm and dry eye, botulinum toxin A injections were effective in relieving blepharospasm but were not successful in treating dry eye syndrome.

https://bjo.bmj.com/content/bjophthalmol/87/1/54.full.pdf

Botulinum toxin A treatment in patients suffering from blepharospasm and dry eye

PURPOSE Exfoliation syndrome (XFS) is characterized by an accumulation of abnormal extracellular material in the anterior part of the eye that frequently leads to increased intraocular pressure and glaucomatous optic neuropathy. Recently, two non-synonymous polymorphisms (rs1048661 G>T and rs3825942 G>A) of lysyl oxidase-like protein 1 (LOXL1), a monoamine oxidase that catalyzes the polymerization of tropoelastin to elastin, were found to be associated with increased risk for XFS and exfoliation glaucoma (XFG). The aim of the present study was to investigate the role of these LOXL1 variants in a Central European cohort of Caucasian patients with XFG. METHODS The present case-control study comprised of 167 unrelated patients with XFG and 170 control subjects. Genotyping of the LOXL1 rs1048661 and rs3825942 polymorphisms was done using polymerase chain reaction. RESULTS The frequency of allele G of rs1048661 as well as rs3825942 was significantly higher in patients than in controls (rs1048661: 0.841 in patients versus 0.669; p<0.001; rs3825942: 0.994 in patients versus 0.817; p<0.001). Odds ratios of 52.1 (95% confidence interval [CI]: 13.85-195.6) and 14.67 (95% CI: 3.81-56.2), respectively, were calculated for the two high-risk haplotypes GG and TG compared to the haplotype GA. CONCLUSIONS Our data confirm the previously reported association between LOXL1 polymorphisms and XFG and extend our knowledge to a Central European population.

/pdf/lysyl-oxidase-like-protein-1-loxl1-gene-polymorphisms-and-558mg5ggun.pdf

Otto Schmut

Papers

Evaluation of the Clinical Course of Dry Eye Syndrome

Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study

Association of complement factor H Y402H gene polymorphism with different subtypes of exudative age-related macular degeneration.

Botulinum toxin A treatment in patients suffering from blepharospasm and dry eye

Lysyl oxidase-like protein 1 (LOXL1) gene polymorphisms and exfoliation glaucoma in a Central European population