The world is facing an epidemic rise in diabetes mellitus (DM) incidence, which is challenging health funders, health systems, clinicians, and patients to understand and respond to a flood of research and knowledge. Evidence-based guidelines provide uniform management recommendations for “average” patients that rarely take into account individual variation in susceptibility to DM, to its complications, and responses to pharmacological and lifestyle interventions. Personalized medicine combines bioinformatics with genomic, proteomic, metabolomic, pharmacogenomic (“omics”) and other new technologies to explore pathophysiology and to characterize more precisely an individual’s risk for disease, as well as response to interventions. In this review we will introduce readers to personalized medicine as applied to DM, in particular the use of clinical, genetic, metabolic, and other markers of risk for DM and its chronic microvascular and macrovascular complications, as well as insights into variations in response to and tolerance of commonly used medications, dietary changes, and exercise. These advances in “omic” information and techniques also provide clues to potential pathophysiological mechanisms underlying DM and its complications.
End-of-life decisions are made daily in intensive care units worldwide. There are numerous factors affecting these decisions, including geographical location as well as religion and attitudes of caregivers, patients, and families. There is a spectrum of end-of-life care options from full continued care, withholding treatment, withdrawing treatment, and active life-ending procedures.
The fetal “programming of adult diseases” has been previously reviewed. The descriptions were comprehensive, dealing with the effects of nutritional deprivation on the development of adult metabolic and cardiovascular diseases. During the past decade, research into this “programming” also expanded to the development of osteoporosis. The present review deals with the imbalance of bone mineral metabolism, “programmed” by maternal/fetal/infantile nutritional deprivation, and is illustrated with a family history from the Budapest Ghetto.
Developments in technology have led to a rapid progress in robotic endocrine surgery applications. With the advent of minimally invasive techniques in thyroid surgery, robot-assisted transaxillary thyroid surgery (RATS) has emerged as one of the most promising approaches. Its main advantages are improved cosmetic outcome, avoiding cervical incisions, thereby increasing patient satisfaction, and improved visualization, arms articulations, and precision, resulting in fewer surgical complications. The main disadvantages are potential new injuries to the brachial plexus, esophagus, and trachea, longer operative time, and increased cost compared to conventional thyroidectomy. In skilled hands, RATS is a safe alternative to conservative thyroidectomy and should be presented to patients with aesthetic concerns. As with any new emerging technique, careful patient selection is crucial, and further evidence must be sought to confirm its indications over time.
Objective: To compare pathologic results obtained via in-office transnasal fiberoptic laryngoscopy (TFL) to those of subsequent direct laryngoscopy in order to assess the accuracy of TFL as a diagnostic tool.
Patients: One hundred and seventeen patients with suspicious laryngeal lesions.
Methods: All patients underwent in-office biopsies. All patients with malignant diagnosis were referred to treatment. All patients with benign diagnosis or carcinoma in situ were referred to direct laryngoscopy for definitive diagnosis. The pathological results of the specimens from both procedures were compared.
Results: Adequate tissue for diagnostic purposes was obtained in 110 of 117 in-office transnasal fiberoptic laryngoscopy biopsies (94.0%). The biopsy results revealed invasive carcinoma in 42 patients (38.2%), carcinoma in situ (CIS) in 17 patients (15.4%), and benign lesions in 51 patients (46.4%). All patients with benign pathologies and carcinoma in situ were referred to biopsy under direct laryngoscopy (five patients refused and were removed from the statistics). The final pathologies identified from the biopsies on direct laryngoscopy revealed that there was an underestimation of the transnasal fiberoptic laryngoscopy results in 33 patients (a false negative rate of 31.4%, 33/105) and an overestimation in one patient. The sensitivity of transnasal fiberoptic laryngoscopy biopsy compared with direct laryngoscopy biopsy was 70.6% and the specificity was 96.7%.
Conclusions: TFL with biopsy is easy, safe, and cost-effective but raises serious doubts about its clinical value due its low sensitivity rate for diagnosing suspicious lesions of the larynx. As such, it is recommended that all patients with a suspicious lesion diagnosed by TFL biopsy as being benign or CIS should be referred to direct laryngoscopy for verification of the findings.
With the discovery of the JAK2V617F mutation in patients with Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) in 2005, major advances have been made in the diagnosis of MPNs, in understanding of their pathogenesis involving the JAK/STAT pathway, and finally in the development of novel therapies targeting this pathway. Nevertheless, it remains unknown which mutations exist in approximately one-third of patients with non-mutated JAK2 or MPL essential thrombocythemia (ET) and primary myelofibrosis (PMF). At the end of 2013, two studies identified recurrent mutations in the gene encoding calreticulin (CALR) using whole-exome sequencing. These mutations were revealed in the majority of ET and PMF patients with non-mutated JAK2 or MPL but not in polycythemia vera patients. Somatic 52-bp deletions (type 1 mutations) and recurrent 5-bp insertions (type 2 mutations) in exon 9 of the CALR gene (the last exon encoding the C-terminal amino acids of the protein calreticulin) were detected and found always to generate frameshift mutations. All detected mutant calreticulin proteins shared a novel amino acid sequence at the C-terminal. Mutations in CALR are acquired early in the clonal history of the disease, and they cause activation of JAK/STAT signaling. The CALR mutations are the second most frequent mutations in Ph- MPN patients after the JAK2V617F mutation, and their detection has significantly improved the diagnostic approach for ET and PMF. The characteristics of the CALR mutations as well as their diagnostic, clinical, and pathogenesis implications are discussed in this review.
Heparanase, a β-D-endoglucuronidase abundant in platelets that was discovered 30 years ago, is an enzyme that cleaves heparan sulfate side chains on the cell surface and in the extracellular matrix. It was later recognized as being a pro-inflammatory and pro-metastatic protein. We had earlier demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. We had shown that heparanase up-regulated the expression of the blood coagulation initiator tissue factor (TF) and interacted with the tissue factor pathway inhibitor (TFPI) on the cell surface membrane of endothelial and tumor cells, leading to dissociation of TFPI and resulting in increased cell surface coagulation activity. Moreover, we have demonstrated that heparanase directly enhanced TF activity which led to increased factor Xa production and subsequent activation of the coagulation system. Recently, heparanase inhibitory peptides derived of TFPI-2 were demonstrated by us to inhibit heparanase procoagulant activity and attenuate sepsis in mouse models.
It has been argued that human evolution has stopped because humans now adapt to their environment via cultural evolution and not biological evolution. However, all organisms adapt to their environment, and humans are no exception. Culture defines much of the human environment, so cultural evolution has actually led to adaptive evolution in humans. Examples are given to illustrate the rapid pace of adaptive evolution in response to cultural innovations. These adaptive responses have important impli-cations for infectious diseases, Mendelian genetic diseases, and systemic diseases in current human populations. Moreover, evolution proceeds by mechanisms other than natural selection. The recent growth in human population size has greatly increased the reservoir of mutational variants in the hu-man gene pool, thereby enhancing the potential for human evolution. The increase in human popula-tion size coupled with our increased capacity to move across the globe has induced a rapid and ongoing evolutionary shift in how genetic variation is distributed within and among local human populations. In particular, genetic differences between human populations are rapidly diminishing and individual het-erozygosity is increasing, with beneficial health effects. Finally, even when cultural evolution eliminates selection on a trait, the trait can still evolve due to natural selection on other traits. Our traits are not isolated, independent units, but rather are integrated into a functional whole, so selection on one trait can cause evolution to occur on another trait, sometimes with mildly maladaptive consequences.
Complex disorders are common in the human population and are caused by interplay between genetic and environmental factors. Therefore the quest for the genetic basis of such disorders has much similar-ity to deciphering the genetic basis of macro-evolutionary processes, such as speciation. Here I discuss conceptual connections between the principles underlying and processes occurring in disease and evo-lution. Special focus is given to the tremendous mitochondrial genetic variability in the population and within individuals and the impact of both types of variability on evolutionary processes and diseases.
Moses Maimonides, the illustrious medieval rabbi and philosopher, dedicated the last decade of his life primarily to medicine. His strong interest in medicine was an integral component of his religious-philosophical teachings and world view. In this paper various sources from his rabbinic writings are presented that explain Maimonides’ motivation regarding and deep appreciation for medicine: (A) The physician fulfills the basic biblical obligation to return lost objects to their owner, for with his knowledge and experience the physician can restore good health to his sick fellow human being; (B) medicine provides a unique opportunity to practice imitatio dei, as it reflects the religious duty to maintain a healthy life-style; (C) as an important natural science, medicine offers tools to recognize, love and fear God. These three aspects address man’s relationship and obligation towards his fellow man, himself and God. Biographical insights supported by additional sources from Maimonides’ writings are discussed.
