Phosphatidylcholine 36:1 concentration decreases along with demyelination in the cuprizone animal model and in post-mortem multiple sclerosis brain tissue.

Multiple sclerosis is a demyelinating and inflammatory disease. Myelin is enriched in lipids, and more specifically, oleic acid. The goal of this study was to evaluate the concentration of oleic acid following demyelination and remyelination in the cuprizone model, test if these changes occurred in specific lipid species, and whether differences in the cuprizone model correlate with changes observed in post-mortem human brains. Eight-week-old C57Bl/6 mice were fed a 0.2% cuprizone diet for 5 weeks and some animals allowed to recover for 11 days. Demyelination, inflammation, and lipid concentrations were measured in the corpus callosum. Standard fatty acid techniques and liquid chromatography combined with tandem mass spectrometry were performed to measure concentrations of fatty acids in total brain lipids and a panel of lipid species within the phosphatidylcholine (PC). Similar measurements were conducted in post-mortem brain tissues of multiple sclerosis patients and were compared to healthy controls. Five weeks of cuprizone administration resulted in demyelination followed by significant remyelination after 11 days of recovery. Compared to control, oleic acid was decreased after 5 weeks of cuprizone treatment and increased during the recovery phase. This decrease in oleic acid was associated with a specific decrease in the PC 36:1 pool. Similar results were observed in human post-mortem brains. Decreases in myelin content in the cuprizone model were accompanied by decreases in oleic acid concentration and is associated with PC 36:1 suggesting that specific lipids could be a potential biomarker for myelin degeneration. The biological relevance of oleic acid for disease progression remains to be verified.

Prognostic significance of major lipids in patients with acute ischemic stroke.

Although dyslipidemia increases the risk for ischemic stroke, previous studies reported conflicting data regarding the association between lipid levels and stroke severity and outcome. To evaluate the predictive value of major lipids in patients with acute ischemic stroke. We prospectively studied 790 consecutive patients who were admitted with acute ischemic stroke (41.0 % males, age 79.4 ± 6.8 years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Moderate/severe stroke was defined as NIHSS ≥5. The outcome was assessed with dependency rates at discharge (modified Rankin scale between 2 and 5) and with in-hospital mortality. Independent predictors of moderate/severe stroke were age (relative risk (RR) 1.05, 95 % confidence interval (CI) 1.02-1.08, p < 0.001), atrial fibrillation (RR 1.71, 95 % CI 1.19-2.47, p < 0.005), heart rate (RR 1.02, 95 % CI 1.01-1.04, p < 0.001), log-triglyceride (TG) levels (RR 0.24, 95 % CI 0.08-0.68, p < 0.01) and high-density lipoprotein cholesterol (HDL-C) levels (RR 0.97, 95 % CI 0.95-0.98, p < 0.001). Major lipids did not predict dependency at discharge. Independent predictors of in-hospital mortality were atrial fibrillation (RR 2.35, 95 % CI 1.09-5.04, p < 0.05), diastolic blood pressure (RR 1.05, 95 % CI 1.02-1.08, p < 0.001), log-TG levels (RR 0.09, 95 % CI 0.01-0.87, p < 0.05) and NIHSS at admission (RR 1.19, 95 % CI 1.14-1.24, p < 0.001). Low-density lipoprotein cholesterol levels were not associated with stroke severity or outcome. Lower TG and HDL-C levels are associated with more severe stroke. Lower TG levels also appear to predict in-hospital mortality in patients with acute ischemic stroke.

Effect of antihypertensive treatment on the long-term outcome of patients discharged after acute ischemic stroke.

We aimed to evaluate the effects of the five main classes of antihypertensive agents on the long-term outcome of 313 consecutive patients discharged after acute ischemic stroke (36.4% males, age 78.5 ± 6.3 years). One year after discharge, the functional status [evaluated with the modified Rankin scale (mRS)], the occurrence of cardiovascular events, and vital status were recorded. Patients prescribed angiotensin receptor blockers (ARBs) had lower mRS than patients not prescribed ARBs (1.7 ± 2.0 vs. 2.9 ± 2.5, respectively; p = 0.006). The rates of adverse outcome (mRS 2-6) and cardiovascular events did not differ between patients prescribed each one of the major classes of antihypertensive agents and those not prescribed the respective class. Patients who were prescribed ARBs had lower risk of death during follow-up than patients who did not receive ARBs (9.4 and 26.9%, respectively; p < 0.05). In binary logistic regression analysis, the only independent predictor of all-cause mortality during follow-up was the mRS at discharge (relative risk 1.69, 95% confidence interval 1.25-2.28; p < 0.001). In conclusion, in patients discharged after acute ischemic stroke, administration of ARBs appears to have a more beneficial effect on long-term functional outcome and all-cause mortality than treatment with other classes of antihypertensive agents.

Treatment with Clopidogrel Prior to Acute Non-Cardioembolic Ischemic Stroke Attenuates Stroke Severity.

BACKGROUND: Clopidogrel reduces the risk of non-cardioembolic ischemic stroke, but it is unclear whether it affects the severity and outcome of stroke. We aimed at evaluating the effect of prior treatment with clopidogrel on acute non-cardioembolic ischemic stroke severity and in-hospital outcome. METHODS: We prospectively studied 608 consecutive patients (39.5% males, age 79.1 ± 6.6 years) who were admitted with acute ischemic stroke. The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Severe stroke was defined as NIHSS ≥21. The outcome was assessed using the dependency rates that prevailed at the time of discharge (i.e. modified Rankin scale between 2 and 5) and with in-hospital mortality. RESULTS: At admission, 397 patients did not have atrial fibrillation or heart valve disease. Among these 397 patients, 69 were receiving monotherapy with clopidogrel prior to stroke, 69 were receiving monotherapy with aspirin and 236 patients were not on any antiplatelet treatment. The prevalence of severe stroke was lower in patients who were receiving clopidogrel than in patients who were receiving aspirin and patients who were not on antiplatelets (1.4, 13.0 and 11.0%, respectively; p < 0.05). Independent predictors of severe stroke at admission were male gender (relative risk (RR) 0.31, 95% CI 0.12-0.78, p < 0.05) and treatment with clopidogrel prior to stroke compared with no antiplatelet treatment (RR 0.13, 95% CI 0.02-0.97, p < 0.05). Treatment with aspirin prior to stroke did not predict severe stroke compared with no antiplatelet treatment (RR 1.24, 95% CI 0.51-2.98, p = NS). The rate of dependency at discharge did not differ between patients who were receiving clopidogrel, patients who were receiving aspirin and those who were not on antiplatelets (57.9, 47.8 and 59.7%, respectively; p = NS). Independent predictors of dependency at discharge were age (RR 1.12, 95% CI 1.05-1.19, p < 0.001) and NIHSS at admission (RR 1.67, 95% CI 1.46-1.92, p < 0.001). In-hospital mortality rate also did not differ between patients who were receiving clopidogrel, patients who were receiving aspirin and those who were not on antiplatelets (4.3, 4.3 and 5.0%, respectively; p = NS). The only independent predictor of in-hospital mortality was NIHSS at admission (RR 1.22, 95% CI 1.14-1.30, p < 0.001). CONCLUSIONS: Treatment with clopidogrel prior to acute non-cardioembolic ischemic stroke attenuates the severity of stroke at admission but does not appear to affect the functional outcome at discharge or the in-hospital mortality of these patients.

Adequacy of preadmission oral anticoagulation with vitamin K antagonists and ischemic stroke severity and outcome in patients with atrial fibrillation.

It is unclear whether vitamin K antagonists affect stroke severity and outcome in patients with atrial fibrillation (AF). We aimed to evaluate this association. We prospectively studied 539 consecutive patients admitted with acute ischemic stroke (41.2 % males, age 78.9 ± 6.6 years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). The outcome was assessed with dependency rates at discharge (modified Rankin scale 2-5) and with in-hospital mortality. 177 patients had a history of AF. The median NIHSS at admission did not differ between patients on acenocoumarol with INR 2.0-3.0, on acenocoumarol with INR < 2.0, on single antiplatelet treatment, on dual antiplatelet treatment, or on no treatment [4 (range 0-26), 13 (0-39), 8 (0-33), 3 (2-23) and 7 (0-33), respectively; p = 0.433]. Dependency rates were lower in patients on acenocoumarol with INR 2.0-3.0 or on dual antiplatelet treatment than in those on acenocoumarol with INR < 2.0, single antiplatelet treatment, or no treatment (20.0, 22.2, 61.5, 58.7 and 68.0 %, respectively; p = 0.024). Independent predictors of dependency were age, NIHSS at admission and history of ischemic stroke. In-hospital mortality did not differ between patients on acenocoumarol with INR 2.0-3.0, on acenocoumarol with INR < 2.0, on single antiplatelet treatment, on dual antiplatelet treatment, or on no treatment (7.7, 18.2, 16.1, 16.7 and 22.2 %, respectively; p = 0.822). In conclusion, optimally anticoagulated patients with AF have more favorable functional outcome after stroke and a trend for less severe stroke whereas patients with subtherapeutic anticoagulation have similar stroke severity and outcome with those on no treatment.

New parameters for identifying subclinical atherosclerosis in patients with primary Sjögren's syndrome: a pilot study.

OBJECTIVES: We investigated sub-clinical cardiovascular involvement in primary Sjögren's syndrome (pSS) patients by means of ADMA, coronary flow reserve (CFR), intima media thickness (cIMT), pulse wave velocity (PWV) and myocardial deformation. METHODS: The study involved 22 outpatients with pSS (6 males, 16 females; mean age 60.14±7.81 years) and no documentable cardiovascular disease, and 22 age- and gender-matched controls. Dipyridamole transthoracic stress echocardiography was used to evaluate wall motion and CFR. A CFR value of <2.5 was considered a sign of impaired coronary function. We also evaluated cIMT arterial stiffness PWV and plasma ADMA levels, and made a speckle tracking echocardiography (STE) analysis. RESULTS: All of the patients were affected by pSS. Although within the normal range, the patients' CFR was lower than that of the controls (median 2.70; IQR 2.40-2.90 vs. 3.20; IQR 3.06-3.33; p<0.0001), whereas their ADMA levels were significantly higher (median 0.81 µM; IQR 0.79-0.85 µM vs. 0.54 µM; IQR 0.52-0.58 µM; p<0.0001). Both left and right PWV values were significantly higher in the patients than in the controls (median 8.8 m/s right and 8.9 m/s left vs. 6.86 and 6.89 m/s), whereas QIMT was substantially similar in the two groups. CONCLUSIONS: Higher ADMA levels suggest the presence of endothelial dysfunction and sub-clinical atherosclerosis in pSS patients, even in the case of a normal CFR. This finding is supported by the PWV values, which were higher in the pSS patients. ADMA levels and PWV values may be useful markers for identifying early endothelial dysfunction in pSS patients.

The changing place of liver biopsy in clinical practice: an audit of an Australian tertiary hospital.

Liver biopsy is an important tool in hepatology, with a role now generally limited to cases of diagnostic uncertainty. A retrospective audit performed at the Royal Melbourne Hospital aimed to identify the indications for liver biopsy and its impact on management. Ten per cent (20/195) of biopsies lacked a strong clinical indication, with hepatology involvement in only 8/20. We recommend prior hepatologist assessment to minimise unnecessary biopsies.

Acute stress promotes effort mobilization for safety-related goals.

Although the acute stress response is a highly adaptive survival mechanism, much remains unknown about how its activation impacts our decisions and actions. Based on its resource-mobilizing function, here we hypothesize that this intricate psychophysiological process may increase the willingness (motivation) to engage in effortful, energy-consuming, actions. Across two experiments (n = 80, n = 84), participants exposed to a validated stress-induction protocol, compared to a no-stress control condition, exhibited an increased willingness to exert physical effort (grip force) in the service of avoiding the possibility of experiencing aversive electrical stimulation (threat-of-shock), but not for the acquisition of rewards (money). Use of computational cognitive models linked this observation to subjective value computations that prioritize safety over the minimization of effort expenditure; especially when facing unlikely threats that can only be neutralized via high levels of grip force. Taken together, these results suggest that activation of the acute stress response can selectively alter the willingness to exert effort for safety-related goals. These findings are relevant for understanding how, under stress, we become motivated to engage in effortful actions aimed at avoiding aversive outcomes.

Asymmetric effects of acute stress on cost and benefit learning.

BACKGROUND: Humans are continuously exposed to stressful challenges in everyday life. Such stressful events trigger a complex physiological reaction - the fight-or-flight response - that can hamper flexible decision-making and learning. Inspired by key neural and peripheral characteristics of the fight-or-flight response, here, we ask whether acute stress changes how humans learn about costs and benefits. METHODS: Healthy adults were randomly exposed to an acute stress (age mean=23.48, 21/40 female) or no-stress control (age mean=23.80, 22/40 female) condition, after which they completed a reinforcement learning task in which they minimize cost (physical effort) and maximize benefits (monetary rewards). During the task pupillometry data were collected. A computational model of cost-benefit reinforcement learning was employed to investigate the effect of acute stress on cost and benefit learning and decision-making. RESULTS: Acute stress improved learning to maximize rewards relative to minimizing physical effort (Condition-by-Trial Type interaction: F(1,78)= 6.53, p = 0.01, n2G= 0.04; reward > effort in stress condition: t(39) = 5.40, p < 0.01). Computational modelling revealed that asymmetric learning could be explained by changes in the learning rates of reward value and action cost [condition-by-learning rate (αR, αE) interaction: F(1,78)= 6.42, p = 0.01, n2G= 0.03; αE> αR in control condition: t(39) = -4.75, p < 0.001]. This process was associated with distinct alterations in pupil size fluctuations. Data and scripts are available (https://osf.io/ydv2q/). CONCLUSIONS: Here we demonstrate that acute stress is associated with asymmetric learning about reward value versus action cost, thereby providing new insights into learning strategies under acute stress, which, depending on the context, may be maladaptive or beneficial. Our pupillometry and physiological results tentatively link asymmetric cost and benefit learning to stress-related changes in catecholamine activity.

Marijuana Use and Health Outcomes in Persons Living With HIV: Protocol for the Marijuana Associated Planning and Long-term Effects (MAPLE) Longitudinal Cohort Study.

BACKGROUND: Marijuana use is common in persons with HIV, but there is limited evidence of its relationship with potential health benefits or harms. OBJECTIVE: The Marijuana Associated Planning and Long-term Effects (MAPLE) study was designed to evaluate the impact of marijuana use on HIV-related health outcomes, cognitive function, and systemic inflammation. METHODS: The MAPLE study is a longitudinal cohort study of participants living with HIV who were recruited from 3 locations in Florida and were either current marijuana users or never regular marijuana users. At enrollment, participants completed questionnaires that included detailed marijuana use assessments, underwent interviewer-administered neurocognitive assessments, and provided blood and urine samples. Ongoing follow-ups included brief telephone assessments (every 3 months), detailed questionnaires (annually), repeated blood and urine samples (2 years), and linkage to medical records and statewide HIV surveillance data. Supplemental measures related to intracellular RNA, COVID-19, Alzheimer disease, and the gut microbiome were added after study initiation. RESULTS: The MAPLE study completed enrollment of 333 persons between 2018 and 2021. The majority of participants in the sample were ≥50 years of age (200/333, 60.1%), male (181/333, 54.4%), cisgender men (173/329, 52.6%), non-Hispanic Black (221/333, 66.4%), and self-reported marijuana users (260/333, 78.1%). Participant follow-up was completed in 2022, with annual updates to HIV surveillance data through at least 2027. CONCLUSIONS: The MAPLE study is the largest cohort specifically designed to understand the use of marijuana and its effects on HIV-related outcomes. The study population has significant diversity across age, sex, gender, and race. The data will help clinicians and public health officials to better understand patterns of marijuana use associated with both positive and negative health outcomes, and may inform recommendations for future clinical trials related to medical marijuana and HIV. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37153.

The Impact of Diversified Farming Practices on Terrestrial Biodiversity Outcomes and Agricultural Yield Worldwide: A Systematic Review Protocol.

The expansion and intensification of agriculture have led to global declines in biodiversity. This paper presents a systematic review protocol to clarify under what management and landscape contexts diversified farming practices are effective at improving outcomes for terrestrial biodiversity, and potential trade-offs or synergies with agricultural yields. The systematic review will be developed following the Reporting Standards for Systematic Evidence Syntheses (ROSES). The review will include articles that compare levels of diversity (e.g., abundance, richness, Shannon's diversity index) of any terrestrial taxon (e.g., arthropods, mammals) in diversified farming systems to levels in simplified farming systems and/or natural habitats, prioritising articles that also report agricultural yields. We will search for relevant peer-reviewed primary studies in two global repositories: Scopus and Web of Science, and among primary studies included in previous meta-analyses that are retrieved from the search. Full-texts of identified articles will be screened using a clear inclusion/exclusion eligibility criteria. All included articles will be assessed to determine their internal validity. A narrative synthesis will be performed to summarize, describe and present the results, and where the articles provide sufficient and appropriate data, we will conduct a quantitative meta-analysis.

A global database of diversified farming effects on biodiversity and yield.

With the Convention on Biological Diversity conference (COP15), United Nations Climate Change Conference (COP26), and United Nations Food Systems Summit, 2021 is a pivotal year for transitioning towards sustainable food systems. Diversified farming systems are key to more sustainable food production. Here we present a global dataset documenting outcomes of diversified farming practices for biodiversity and yields compiled following best standards for systematic review of primary studies and specifically designed for use in meta-analysis. The dataset includes 4076 comparisons of biodiversity outcomes and 1214 of yield in diversified farming systems compared to one of two reference systems. It contains evidence from 48 countries of effects on species from 33 taxonomic orders (spanning insects, plants, birds, mammals, eukaryotes, annelids, fungi, and bacteria) of diversified farming systems producing annual or perennial crops across 12 commodity groups. The dataset presented provides a resource for researchers and practitioners to easily access information on where diversified farming systems effectively contribute to biodiversity and food production outcomes.

Agrobiodiversity Index scores show agrobiodiversity is underutilized in national food systems.

The diversity of plants, animals and microorganisms that directly or indirectly support food and agriculture is critical to achieving healthy diets and agroecosystems. Here we present the Agrobiodiversity Index (based on 22 indicators), which provides a monitoring framework and informs food systems policy. Agrobiodiversity Index calculations for 80 countries reveal a moderate mean agrobiodiversity status score (56.0 out of 100), a moderate mean agrobiodiversity action score (47.8 out of 100) and a low mean agrobiodiversity commitment score (21.4 out of 100), indicating that much stronger commitments and concrete actions are needed to enhance agrobiodiversity across the food system. Mean agrobiodiversity status scores in consumption and conservation are 14-82% higher in developed countries than in developing countries, while scores in production are consistently low across least developed, developing and developed countries. We also found an absence of globally consistent data for several important components of agrobiodiversity, including varietal, functional and underutilized species diversity.

Complexation of Mo in FLiNaK Molten Salt: Insight from Ab Initio Molecular Dynamics.

Online extraction of fission products, such as the medical isotope Mo-99, is a key advantage of the proposed molten salt nuclear reactor design. The chemical and structural behavior of Mo solvated in fluoride salt has been relatively unknown. Ab initio molecular dynamics simulations were employed to examine the behavior of molybdenum in the molten salt FLiNaK (LiF-NaF-KF) for oxidation states between 0 and 6+. Mo complexation was found to vary with the Mo oxidation state, with lower oxidation states tending to result in complexes with more molybdenum ions. Complexes containing multiple Mo ions were observed for all Mo oxidation states studied except 5+ and 6+. A relationship between the solubility of a complex and electronic isolation of a complex in a molten salt is explored using the Bader atoms in molecule electron density partitioning scheme, with more volatile complexes exhibiting greater electronic isolation. The impacts of UF4 and H2O on the predominant molybdenum species are also considered. While no impacts on Mo behavior by UF4 were observed, Mo-O interactions may inhibit the formation of complexes containing multiple Mo ions.

Preoperative investigations for metastatic staging of colon and rectal cancer across multiple centres--what is current practice?

OBJECTIVE: The optimal strategy for elective distant staging of colorectal carcinoma (CRC) has yet to be defined, with current guidelines based on small and limited series. One specific issue requiring review is the value of routine computerized tomographic (CT) chest examination. Also lacking is data on current routine clinical practice. METHOD: A retrospective chart review of consecutive cases of elective surgery for CRC from five hospitals. RESULTS: Two hundred and fifty-seven cases were reviewed, 128 colon and 129 rectal primaries. 164 (64%) of patients overall, ranging from 45% to 88% across the individual centres, had a preoperative serum CEA level performed. CT abdomen/pelvis was performed in 222 (86%) of cases, ranging from 69% to 98% per centre. CT chest was performed in 95 (37%) of cases, 47% of rectal vs 29% of colon cancers (P = 0.004). In 17 cases (18%) CT chest examinations revealed abnormalities suspicious for metastatic disease, leading to a change in management in six (35%) of these cases. Of the 17 cases with an abnormal CT chest, in only 5 of the 14 (36%) where carcinoembryonic antigen (CEA) levels were also recorded was this increased, and in only three (21%) was this markedly (> 10 microg/l) elevated. CONCLUSIONS: Substantial variability exists in the preoperative evaluation of patients with CRC. Many patients do not have a CEA and/or abdominal imaging performed. Where performed, CT chest revealed suspicious findings in a significant number of patients, the vast majority of whom had a normal or near normal CEA. Future studies are required to define optimal preoperative staging.

Image-guided, stereotactic perforator flap surgery: a prospective comparison of current techniques and review of the literature.

BACKGROUND: Image-guided stereotaxy is a recent advancement in imaging technology, allowing computer guidance to aid surgical planning and accuracy. Despite the use of multiple techniques for patient registration in several surgical specialities, only fiducial marker registration has been described for use in soft tissue reconstructive surgery. The current study comprises an evaluation of the current techniques available for this purpose. METHODS: A cohort of nine consecutive patients planned for elective free flaps were recruited, with the first five patients (four for the abdominal wall and one anterolateral thigh donor site) undergoing fiducial marker registration with a variable number of fiducial markers in order to determine the optimal number of fiducial markers to be used. Four subsequent patients undergoing perforator flap surgery underwent registration using three available registration modalities: fiducial marker registration, surface matching pointer/landmark and surface matching laser registration. RESULTS: For the abdominal wall, registration was not able to be achieved with five fiducial markers, and was successfully achieved in all cases with either six or seven fiducial markers. For the anterolateral thigh, registration was achieved with either nine or ten markers. The four patients who also underwent surface-landmark registration and 'Z-touch' laser surface matching registration all failed the registration process. CONCLUSION: Stereotactic navigation is a useful adjunct to the preoperative imaging of perforator flaps. Fiducial marker registration was able to be achieved in all cases, can be successfully achieved with a low and predictable number of fiducial markers, is highly accurate, and was the only reliable registration process in our experience.

The mechanisms of acute interstitial nephritis in the era of immune checkpoint inhibitors in melanoma.

Treatment with immune checkpoint inhibitors (ICIs) has improved the prognosis of patients with a number of types of cancer, but the frequent development of immune-related adverse effects (irAEs) can worsen the outcome. The most common irAEs involve the gastrointestinal, cutaneous, and endocrine systems, but nephrotoxicity, resulting from damage to the tubule-interstitial compartment, may occur in some patients. The early phases of acute interstitial nephritis (AIN) are characterized by systemic symptoms that indicate a poor clinical state as well as a mild deterioration of renal function. Tubular injury is due to a direct effect mediated by cytotoxic CD8+ T cells, which sustain the local production of pro-inflammatory cytokines that progressively impair renal function. The treatment of AIN is mainly based on high-dose steroids, which in most instances leads to the recovery of renal function. However, the premature discontinuation of ICI therapy may prevent the impact of treatment on the clinical progression of the malignancy. Adequately addressing irAEs requires a standardized therapy that is based on the results of large clinical trials.

Clinical, cytogenetic, and molecular findings in a patient with ring chromosome 4: case report and literature review.

BACKGROUND: Since 1969, 49 cases have been presented on ring chromosome 4. All of these cases have been characterized for the loss of genetic material. The genes located in these chromosomal regions are related to the phenotype. CASE PRESENTATION: A 10-year-old Ecuadorian Mestizo girl with ring chromosome 4 was clinically, cytogenetically and molecularly analysed. Clinical examination revealed congenital anomalies, including microcephaly, prominent nose, micrognathia, low set ears, bilateral clinodactyly of the fifth finger, small sacrococcygeal dimple, short stature and mental retardation. Cytogenetic studies showed a mosaic karyotype, mos 46,XX,r(4)(p16.3q35.2)/46,XX, with a ring chromosome 4 from 75 to 79% in three studies conducted over ten years. These results were confirmed by fluorescence in situ hybridization (FISH). Loss of 1.7 Mb and gain of 342 kb in 4p16.3 and loss of 3 Mb in 4q35.2 were identified by high-resolution mapping array. CONCLUSION: Most cases with ring chromosome 4 have deletion of genetic material in terminal regions; however, our case has inv dup del rearrangement in the ring chromosome formation. Heterogeneous clinical features in all cases reviewed are related to the amount of genetic material lost or gained. The application of several techniques can increase our knowledge of ring chromosome 4 and its deviations from typical "ring syndrome."