Multiple branch retinal arteriolar occlusions associated with smallpox vaccination

We describe a rare combination of multiple multiple branch retinal arteriolar occlusions (BRAO) and encephalopathy, which developed in an adult male 10 days after smallpox vaccination. A 53-year-old physician presented with sudden temporal visual field loss in the left eye. Ten days earlier he had received a smallpox vaccination. Hyperbaric oxygen was administered because of suspected BRAO. Examination on day 3 revealed a decrease in visual acuity and loss of visual field. Fundoscopy of the left eye disclosed a retinal infarct in the inferior macula and multiple cotton wool spots over the entire posterior pole. Fluorescein angiography showed delayed arterial filling and multiple non-perfused areas. Magnetic resonance imaging of the brain disclosed white matter focal lesions. Neurological examination was normal. Audiological examination revealed mild hearing loss caused by an old phonic trauma. A combination of intravenous methylprednisolone and immunoglobulins, recommended for the treatment of Susac syndrome, was administered. At the follow-up visit 3 months later, visual acuity in the left eye improved, fundoscopy showed resolution of the cotton wool spots and temporal disc pallor, and the visual field was substantially restored.     

ZnT-1 protects HL-1 cells from simulated ischemia–reperfusion through activation of Ras–ERK signaling

Activation of ERK signaling may promote cardioprotection from ischemia-reperfusion (I/R) injury. ZnT-1, a protein that confers resistance from zinc toxicity, was found to interact with Raf-1 kinase through its C-terminal domain, leading to downstream activation of ERK. In the present study, we evaluated the effects of ZnT-1 in cultured murine cardiomyocytes (HL-1 cells) that were exposed to simulated-I/R. Cellular injury was evaluated by lactate dehydrogenase (LDH) release and by staining for pro-apoptotic caspase activation. Overexpression of ZnT-1 markedly reduced LDH release and caspase activation following I/R. Knockdown of endogenous ZnT-1 augmented the I/R-induced release of LDH and increased caspase activation following I/R. Phospho-ERK levels were significantly increased following I/R in cells overexpressing ZnT-1, while knockdown of ZnT-1 reduced phospho-ERK levels. Pretreatment of cells with the MEK inhibitor PD98059 abolished the protective effect of ZnT-1 following I/R. Accordingly, a truncated form of ZnT-1 lacking the C-terminal domain failed to induce ERK activation and did not protect the cells from I/R injury. In contrast, expression of the C-terminal domain by itself was sufficient to induce ERK activation and I/R protection. Interestingly, the C-terminal of the ZnT-1 did not have protective effect against the toxicity of zinc. In the isolated rat heart, global ischemic injury rapidly increased the endogenous levels of ZnT-1. However, following reperfusion ZnT-1 levels were found to be decreased. Our findings indicate that ZnT-1 may have important role in the ischemic myocardium through its ability to interact with Raf-1 kinase.     

Nursing and midwifery education, practice, and issues in Israel

Nurses deliver most of Israel's healthcare services, yet its nurse per population ratio is only 5.9 per 1000, one of the lowest in the developed world. For several years, the managers of the profession have been pushing to upgrade nursing and to move it into the academic sphere. The semiskilled qualification of the practical nurse has been eliminated and training programs for registered nurses are being transformed from diploma training to academic degree programs. A midwifery license is accessible only to registered nurses who take a further 1 year of advanced training and sit the State Midwifery Licensing Examination. Most deliveries in Israel are carried out by midwives. Alongside the Western-standard hospital system there operates both a well-developed community nursing network and a strong mother-and-child clinic system. The acute shortage of nurses in Israel is now coinciding with a rising number of academic job-seekers, which has encouraged the Ministry of Health to offer university graduates a career-change program. Special scholarships are on offer in return for a 4 year commitment to work in nursing after completing an accelerated training curriculum (2.5 years instead of the usual 3 years), plus a starting monthly wage that is higher than the national average wage.     

Glucagonoma and the glucagonoma syndrome - cumulative experience with an elusive endocrine tumour

Objective Glucagonoma is a pancreatic neuroendocrine tumour that arises from alpha cells in the pancreas and is often accompanied by a characteristic clinical syndrome. Design In this report, we present the cumulative experience and clinical characteristics of six patients diagnosed with glucagonoma and the glucagonoma syndrome and treated at our centre during the past 25 years. Results Although the course of the disease was variable, some features were similar. The median age at diagnosis was 53·5 years; the median time from onset of symptoms to diagnosis was 39 months. Presenting symptoms were as follows: weight loss 5/6 (83%), necrotizing migratory erythema (NME) 5/6 (83%), diabetes mellitus 4/6 (66%) and diarrhoea, weakness and thrombosis 2/6 (33%). Plasma glucagon was elevated in all patients upon diagnosis (range 200–10 000 pm ; N < 50). Skin biopsy was diagnostic only in 1/6 specimens obtained, even after revision. Metastatic disease developed in all patients; 4/6 initially presented with hepatic metastasis. All patient symptoms responded to somatostatin analogue therapy. In 4/6, the NME responded to amino acid solutions. Other modes of therapy were as follows: surgery in 3/6 patients, peptide receptor radioligand therapy with ⁹⁰Y‐DOTATOC (PRRT) in 3/6 patients (two responses) and chemotherapy in three patients (two responded). Four out of six patients died of the disease, and median survival time was 6·25 years (range 2–11) from diagnosis and 8 years (range 8–16) from initial symptoms. Five‐year survival was 66%. Conclusion Our data indicate that somatostatin analogues and an aggressive surgical approach offer symptom relief and tumour control. Among other available treatment modalities, PRRT seems to hold the most promise.     

P wave dispersion in familial Mediterranean fever

Familial Mediterranean fever (FMF) is a hereditary disease characterized by recurrent and self-terminated attacks of fever and polyserositis. A recent study found that FMF patients had an abnormally high P wave duration and P wave dispersion, markers for supraventricular arrhythmogenicity. The aim of our study was to further evaluate atrial dispersion in FMF patients. The study group consisted of 26 patients with uncomplicated FMF and age- and sex-matched control subjects. All participants underwent 12-lead electrocardiography under strict standards. P wave length and P wave dispersion were computed from a randomly selected beat and from an averaged beat constructed from 7 to 12 beats, included in a 10-s ECG. No statistically significant differences were found between the groups in minimal, maximal, and average P wave duration and P wave dispersion calculated either from a random beat or averaged beats. During 6 months of follow-up, no supraventricular arrhythmias were documented in either group. FMF patients who are continuously treated with colchicine and do not develop amyloidosis have normal atrial conduction parameters and therefore seemingly do not have an increased electrocardiographic risk of atrial fibrillation.     

Adolescent obesity and adult male breast cancer in a cohort of 1,382,093 men

Male breast cancer (MBC) accounts for 1% of all breast cancer. Adult obesity and tallness are risk factors for MBC, but the role of adolescent fatness is largely unknown. We aimed to assess the association between body mass index (BMI) in adolescence and the incidence of MBC in a large cohort of 16‐ to 19‐year‐old Israeli males. 1,382,093 Jewish Israeli males aged 16–19 who underwent anthropometric measurements, a general intelligence test (GIT) and other examinations during 1967–2011, were followed up to December 31, 2012 for MBC incidence. Cox proportional hazards models assessed the association between adolescent BMI (as WHO BMI categories and as age‐specific CDC percentiles) and time to MBC diagnosis, adjusting for sociodemographic covariates. Of 100 MBC cases diagnosed during 29,386,233 person‐years of follow‐up, 97 were included in multivariable analyses. Compared to “healthy” BMI (18.5–24.9 kg/m²) and adjusted for year of birth, country of origin and GIT score, higher adolescent BMI was associated with higher MBC risk: hazard ratio (HR) = 2.01 (95% confidence interval [CI] 1.14–3.55, p = 0.015) in overweight (25.0 ≤ BMI < 30.0 kg/m²) adolescents; and HR = 4.97 (95%CI 2.14–11.53, p = 0.0002) in obese (BMI ≥ 30.0 kg/m²) adolescents. When CDC age‐specific BMI percentiles were assessed results were similar and statistically significant for obesity. In addition, low (vs. high) GIT score (HR = 4.76, 95%CI 1.96–12.50, p = 0.001) and European (vs. west‐Asian) origin (HR = 1.99, 95%CI 1.19–3.34, p = 0.009) were independent predictors of MBC. Measured adolescent overweight and obesity are associated with increased risk of MBC, suggesting a modifiable risk factor potentially allowing for early intervention. The novel association with cognitive function should be further explored.     

The effects of digital filtering on mismatch negativity in wakefulness and slow-wave sleep

The mismatch negativity (MMN) is a response to a deviant auditory stimulus that occurs infrequently in a sequence of otherwise repetitive, homogeneous standard auditory stimuli. The MMN is presumed automatic and independent of conscious awareness. Recording of the MMN during unconscious states may be problematic. The frequency content of the long-lasting MMN may overlap and summate with other event-related slow potentials and low-frequency background electroencephalogram (EEG) activity. The purpose of this study is to determine the optimal filter settings for recording the MMN during unconscious states. Auditory event-related potentials (ERPs) were recorded from eight subjects in an oddball paradigm during wakefulness and Stages 3 and 4 of sleep [slow-wave sleep (SWS)] using a 0.16-35 Hz analogue bandpass. Deviant probability was 0.033. Stimulus-onset asynchrony was 150 ms. The EEG data were subsequently digitally filtered in the frequency domain. The low-pass filter was set at either 24, 12 or 6 Hz, and the high-pass filter at either 1, 2, 3 or 4 Hz. Applying a low-pass filter down to 12 Hz had a minimal impact on the waking or sleeping MMN amplitude. On the other hand, increasing the high-pass setting from 2 to 3 Hz permitted the visualization of the MMN recorded during sleep. The 4 Hz filter showed a similar trend but also markedly attenuated the amplitude of the waking MMN. A high-pass setting of 3 Hz provides a reasonable compromise. It has only a slight effect on the MMN when the subject is conscious, but still attenuates most of the unwanted slow potential activity when the subject enters SWS.     

Dysfunctions of innate and adaptive immune tumor microenvironment in Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by malignant lymphoplasmacytic cells in the bone marrow (BM). To dissect the pathophysiology of WM, we evaluated clonal cells by mapping of B cell lymphomagenesis with adaptive and innate immune tumor microenvironment (TME) in the BM of WM patients using mass cytometry (CyTOF). In-depth immunophenotypic profiling of WM cells exhibited profound expansion of clonal cells in both unswitched and switched memory B cells and also plasma cells with aberrant expression variations. WM B lymphomagenesis was associated with reduction of most B cell precursors assessed with the same clonally restricted light chain and phenotypic changes. The immune TME was infiltrated by mature monocytes, neutrophils and adaptive T cells, preferentially subsets of effector T helper, effector CTL and effector memory CTL cells that were associated with superior overall survival (OS), in contrast to progenitors of T cells and myeloid/monocytic lineage subsets that were suppressed in WM cohort. Moreover, decrease in immature B and NKT cells was related to worse OS in WM patients. Innate and adaptive immune subsets of WM TME were modulated by immune checkpoints, including PD-1/PD-L1&PD-L2, TIGIT/PVR, CD137/CD137-L, CTLA-4, BTLA and KIR expression. The response of ibrutinib treatment to the reduction of clonal memory B cell was associated with high levels of immature B cells and effector memory CTL cells. Our study demonstrates that CyTOF technology is a powerful approach for characterizing the pathophysiology of WM at various stages, predicting patient risk and monitoring the effectiveness of treatment strategies.