Dominant negative mutations in STAT3, a critical signaling molecule and transcription factor in multiple organ systems, lead to a rare monogenic disease called the STAT3 loss-of-function, autosomal dominant hyper-IgE syndrome (STAT3LOF AD-HIES). The original name for this syndrome, Job’s syndrome, was derived from the observation that patients had a propensity to develop skin boils, reminiscent of the affliction cast upon the biblical Job. Many fascinating observations have been made regarding the pathogenesis of the disease and the role STAT3 plays in human health and disease. Additionally, quite a few phenotypic descriptions from the Book of Job are similar to those seen in patients with STAT3LOF AD-HIES, beyond just the boils. This complex multisystem genetic disorder is a challenge clinically and scientifically, but it also brings into question how we approach genetic syndromes beyond just the technical aspects of research and treatment.
The porphyrias are a group of rare metabolic disorders, inherited or acquired, along the heme biosynthetic pathway, which could manifest with neurovisceral and/or cutaneous symptoms, depending on the defective enzyme. Neurovisceral porphyrias are characterized by acute attacks, in which excessive heme production is induced following exposure to a trigger. An acute attack usually presents with severe abdominal pain, vomiting, and tachycardia. Other symptoms which could appear include hypertension, hyponatremia, peripheral neuropathy, and mild mental symptoms. In severe attacks there could be severe symptoms including seizures and psychosis. If untreated, the attack might become very severe, affecting the peripheral, central, and autonomic nervous system, leading to paralysis, respiratory failure, hyponatremia, coma, and even death. From the biochemical point of view, acute attacks are involved with increased levels of precursors in the heme biosynthetic pathway, up to the deficient step. Of these precursors, aminolevulinic acid (ALA) is considered to be neurotoxic. Treatment is directed to reduce ALA production by reducing the activity of the enzyme aminolevulinate synthase (ALAS)—most effectively by heme therapy. Cutaneous symptoms are a consequence of elevated porphyrins in the blood stream. These porphyrins react to light; therefore sun-exposed areas are affected, producing fragile erosive skin lesions in porphyria cutanea tarda (PCT) or non-scarring stinging and burning symptoms in erythropoietic protoporphyria (EPP). Unlike the most common neurovisceral porphyria, acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP) can have cutaneous symptoms as well. Differentiating them from other cutaneous porphyrias is essential for accurate diagnosis, treatment, and patient recommendations.
The strong relationship between cardiovascular diseases (CVD), atherosclerosis, and endogenous or exogenous lipids has been recognized for decades, underestimating the contribution of other dietary components, such as amino acids, to the initiation of the underlying inflammatory disease. Recently, specific amino acids have been associated with incident cardiovascular disorders, suggesting their significant role in the pathogenesis of CVD. Special attention has been paid to the group of branched-chain amino acids (BCAA), leucine, isoleucine, and valine, since their plasma values are frequently found in high concentrations in individuals with CVD risk. Nevertheless, dietary BCAA, leucine in particular, have been associated with improved indicators of atherosclerosis. Therefore, their potential role in the process of atherogenesis and concomitant CVD development remains unclear. Macrophages play pivotal roles in the development of atherosclerosis. They can accumulate high amounts of circulating lipids, through a process known as macrophage foam cell formation, and initiate the atherogenesis process. We have recently screened for anti- or pro-atherogenic amino acids in the macrophage model system. Our study showed that glycine, cysteine, alanine, leucine, glutamate, and glutamine significantly affected macrophage atherogenicity mainly through modulation of the cellular triglyceride metabolism. The anti-atherogenic properties of glycine and leucine, and the pro-atherogenic effects of glutamine, were also confirmed in vivo. Further investigation is warranted to define the role of these amino acids in atherosclerosis and CVD, which may serve as a basis for the development of anti-atherogenic nutritional and therapeutic approaches.
BACKGROUND: The energy crisis hypothesis, which is a widely accepted model for the pathogenesis of myofascial pain, has been corroborated by experimental observations. However, the nature of the insult leading to the energy crisis remains elusive. A commonly cited model for this insult is the Cinderella hypothesis, suggesting that hierarchical recruitment of motor units leads to a disproportional load on small units, thus driving them towards an energy crisis. New findings cast doubt on this model, showing that in postural muscles motor units are recruited in rotation, rather than in a hierarchical order, precluding the formation of the so-called Cinderella units.
OBJECTIVE: To explore the influence of common myofascial predisposing factors such as muscle load and muscle strength on the relaxation time of postural muscle motor units, assuming they are recruited in rotation.
METHODS: A stochastic model of a postural skeletal muscle was developed which integrates the energy crisis model and motor unit rotation patterns observed in postural muscles. Postulating that adequate relaxation time is essential for the energetic replenishment of motor units, we explored the influence of different parameters on the relaxation time of individual motor units under varying conditions of muscle loads and muscle strengths.
RESULTS: The motor unit relaxation/contraction time ratio decreases with elevated muscle loads and with decreased total muscle strength.
Conclusions: In a model of a postural muscle, in which motor units are recruited in rotation, common predisposing factors of myofascial pain, such as increased muscle load and decreased muscle force, lead to shortened motor unit relaxation periods.
Chemotherapy-associated myocardial toxicity is increasingly recognized with the expanding armamentari¬um of novel chemotherapeutic agents. The onset of cardiotoxicity during cancer therapy represents a major concern and often involves clinical uncertainties and complex therapeutic decisions, reflecting a compro¬mise between potential benefits and harm. Furthermore, the improved cancer survival has led to cardio¬vascular complications becoming clinically relevant, potentially contributing to premature morbidity and mortality among cancer survivors. Specific higher-risk populations of cancer patients can benefit from pre¬vention and screening measures during the course of cancer therapies. The pathobiology of chemotherapy-induced myocardial dysfunction is complex, and the individual patient risk for heart failure entails a multifactorial interaction between the selected chemotherapeutic regimen, traditional cardiovascular risk factors, and individual susceptibility. Treatment with several specific chemotherapeutic agents, including anthracyclines, proteasome inhibitors, epidermal growth factor receptor inhibitors, vascular endothelial growth factor inhibitors, and immune checkpoint inhibitors imparts increased risk for cardiotoxicity that results from specific therapy-related mechanisms. We review the pathophysiology, risk factors, and imaging considerations as well as patient surveillance, prevention, and treatment approaches to mitigate cardiotox¬icity prior, during, and after chemotherapy. The complexity of decision-making in these patients requires viable discussion and partnership between cardiologists and oncologists aiming together to eradicate cancer while preventing cardiotoxic sequelae.
Background: The importance of emotional intelligence (EI) to the success of health professionals has been increasingly acknowledged. Concurrently, medical schools have begun integrating non-cognitive measures in candidate selection processes. The question remains whether these newly added processes correctly assess EI skills.
Objectives: Measuring EI levels among medical students; examining the correlations between participants’ EI levels and their scores on the non-cognitive MOR test; and exploring students’ attitudes regarding the importance of EI in medical practice.
Methods: The study included 111 first-year and sixth-year students at the Faculty of Medicine at the Technion, Haifa, Israel. Emotional intelligence was assessed by the Bar-On EQ-i 2.0, and MOR evaluation scores were provided by the faculty. An additional questionnaire was designed to rate students’ attitudes toward the importance of EI to the success of medical doctors (MDs).
Results: No significant correlations were found between MOR test scores and EI evaluation scores. Of the 15 EI competencies evaluated, mean scores for flexibility, problem-solving, and independence were lowest for both the first-year and the sixth-year study groups. No differences in EI levels between first-year and sixth-year students were found. Both groups of students considered EI to be highly important to their success as MDs.
Conclusions: While further studies of the links between MOR tests and EI are required, the current findings indicate that MOR test scores may not be predictive of medical students’ EI levels and vice versa. As previous evidence suggests that EI contributes to professional success and to better outcomes in the field of medicine, integrating it into selection processes for medical students and into the curricula in medical schools is recommended.
We are proud to introduce you to the Fifteenth Annual Rambam Research Day, now established as a key annual event at Rambam Health Care Campus, Haifa, Israel, reflecting the diverse research activities on our campus.
Background: Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy in India. The aggressiveness of OSCC is analyzed not only based on the dysplastic features and tumor infiltration pattern, but also by means of the stromal changes that pave the way for an invasion into the connective tissue. The role of elastic fibers in the progression of OSCC is still unknown because of sparse literature and the masking effect of overlying inflammatory cells and the lower number of elastic fibers in the lamina propria. The present study provides further insight into the qualitative assessment of elastic fibers in various grades of dysplasia and OSCC.
Objectives: To analyze the morphological changes exhibited by the elastic fibers in epithelial dysplasia and OSCC.
Materials and methods: Two sections were cut from each of 60 samples of varying grades of OSCC and 60 samples of varying grades of epithelial dysplasia followed by staining with hematoxylin and eosin and Verhoeff–Van Gieson stain.
Results: Statistically significant results were obtained for qualitative analysis of elastic fibers. A change in density and orientation to overlying epithelium and tumor islands was seen on progressing from well-differentiated to poorly differentiated OSCC and in progressing grades of dysplasia.
Conclusion: The uniqueness of this study lies in the exploration of elastic fibers in dysplasia and well-differentiated OSCC, a less explored field. The study of the connective tissue stromal changes can be used as an adjunct to histological grading.
Objective: The World Health Organization’s (WHO) guidelines for cancer pain management were intentionally made simple in order to be widely implemented by all physicians treating cancer patients. Referrals to pain specialists are advised if pain does not improve within a short time. The present study examined whether or not a reasonable use of the WHO guideline was made by non-pain specialists prior to referral of patients with cancer-related pain to a pain clinic.
Methods: Cancer patients referred to a pain specialist completed several questionnaires including demographics, medical history, and cancer-related pain; the short-form McGill Pain Questionnaire (SF-MPQ); and the Short Form Health Survey SF-12. Data from referral letters and medical records were obtained. Treatments recommended by pain specialists were recorded and categorized as “unjustified” if they were within the WHO ladder framework, or “justified” if they included additional treatments.
Results: Seventy-three patients (44 women, 29 men) aged 55 years (range, 25–85) participated in the study. Their pain lasted for a mean of 6 (1–192) months. Mean pain intensity scores on a 0–10 numerical rating scale were 7 (2–10) at rest and 8 (3–10) upon movement. Most patients complied with their referring physician’s recommendations and consumed opioids. Adverse events were frequent. No significant correlation was found between the WHO analgesic medication step used and mean pain levels reported. There were 63 patient referrals (85%) categorized as “unjustified,” whereas only 11 patients (15%) required “justified” interventions.
Conclusions: These findings imply that analgesic treatment within the WHO framework was not reasonably utilized by non-pain specialists before referring patients to pain clinics.
Objective: The aim of the present study was to determine and compare the expression pattern and localization of nestin, in an attempt to explore its role in oral carcinogenesis.
Methods: Western blot and immunohistochemistry analysis were performed to study the expression pattern of nestin in normal mucosa, leukoplakia, and oral squamous cell carcinoma samples. Nestin expres¬sion was evaluated in the keratinocytes and blood vessels of all the samples and compared with various clinico-pathological parameters.
Results: Nestin expression was increased in samples of leukoplakia and oral squamous cell carcinoma when compared with normal mucosa. Among leukoplakia samples, the expression was increased in cases without dysplasia compared to cases with dysplastic features. In cases of oral squamous cell carcinoma, the expression of nestin was found to be decreased with the loss of differentiation. Neoangiogenesis status determined by nestin expression showed an increasing expression from normal mucosa through leuko-plakia, to oral squamous cell carcinoma.
Conclusion: This study has two major findings: 1) identification of nestin as an effective indicator of neo-angiogenesis, and 2) nestin may be used as a marker in predicting the early changes in oral carcinogenesis.
