Instrumental Workup Research Articles

Arterial stiffness in non-alcoholic fatty liver disease

Background. The presence of metabolic-associated pathology, namely obesity, diabetes mellitus, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD), significantly accelerates the development of the cardiovascular continuum. This is associated with an increased risk of major cardiovascular events (myocardial infarction, stroke). An important organ damage in hypertension (HTN) is the remodeling of small arteries and an increase in stiffness of large arteries. The relationship between NAFLD, dyslipidemia, hypertriglyceridemia, obesity (especially abdominal), diabetes, and HTN is well studied, but there is a lack of clinical studies examining changes in arterial stiffness in NAFLD. Aim of the research was to study the parameters of arterial stiffness in patients with NAFLD. Materials and methods. Eighty-two Caucasian patients with NAFLD (mean age (56.8 ± 1.1) years, 59.8 % men) were enrolled. Participants were divided into two groups: group 1 (n = 44) — NAFLD and concomitant HTN, group 2 (n = 38) — HTN without NAFLD. All patients underwent a standard general clinical examination, laboratory and instrumental work-up. In addition, all patients were assessed for the parameters of arterial stiffness via non-invasive arteriography. Results. Patients with NAFLD had significantly higher office systolic and diastolic blood pressure (by 15.2 and 10.4 %, respectively, p < 0.01) despite comparable drug therapy. The same trends were observed in relation to the central aortic pressure, which was 19.3 % higher in patients with NAFLD (p < 0.01), and central pulse pressure that was 35.9 % higher than in patients without NAFLD (p < 0.01). Brachial artery augmentation index in NAFLD turned to be elevated compared to patients without NAFLD (p < 0.01), but aortic augmentation index was comparable between groups. The return time interval in group 1 was 50.3 % higher than in group 2 (p < 0.01). Finally, patients with NAFLD had a significant increase in pulse wave velocity by 52.3 % compared to those without NAFLD with average value exceeding 12 m/sec (p < 0.01). Conclusions. There is an association between NAFLD and worse indices of arterial stiffness in patients with concomitant HTN.

Plasma biomarkers increase diagnostic confidence in patients with Alzheimer’s disease or frontotemporal lobar degeneration

BackgroundThe recent development of techniques to assess plasma biomarkers has changed the way the research community envisions the future of diagnosis and management of Alzheimer’s disease (AD) and other neurodegenerative disorders. This work aims to provide real world evidence on the clinical impact of plasma biomarkers in an academic tertiary care center.MethodsAnonymized clinical reports of patients diagnosed with AD or Frontotemporal Lobar Degeneration with available plasma biomarkers (Aβ42, Aβ42/Aβ40, p-tau181, p-tau231, NfL, GFAP) were independently assessed by two neurologists who expressed diagnosis and diagnostic confidence three times: (T0) at baseline based on the information collected during the first visit, (T1) after plasma biomarkers, and (T2) after traditional biomarkers (when available). Finally, we assessed whether clinicians’ interpretation of plasma biomarkers and the consequent clinical impact are consistent with the final diagnosis, determined after the conclusion of the diagnostic clinical and instrumental work-up by the actual managing physicians who had complete access to all available information.ResultsClinicians assessed 122 reports, and their concordance ranged from 81 to 91% at the three time points. At T1, the presentation of plasma biomarkers resulted in a change of diagnosis in 2% (2/122, p = 1.00) of cases, and in increased diagnostic confidence in 76% (91/120, p < 0.001) of cases with confirmed diagnosis. The change in diagnosis and the increase in diagnostic confidence after plasma biomarkers were consistent with the final diagnosis in 100% (2/2) and 81% (74/91) of cases, respectively. At T2, the presentation of traditional biomarkers resulted in a further change of diagnosis in 13% (12/94, p = 0.149) of cases, and in increased diagnostic confidence in 88% (72/82, p < 0.001) of cases with confirmed diagnosis.ConclusionsIn an academic tertiary care center, plasma biomarkers supported clinicians by increasing their diagnostic confidence in most cases, despite a negligible impact on diagnosis. Future prospective studies are needed to assess the full potential of plasma biomarkers on clinical grounds.

Circulating tumor DNA in patients with locally advanced rectal cancer treated with multimodal treatment.

The management of locally advanced rectal cancer (LARC) relies on a multimodal approach. Neither instrumental work-up nor molecular biomarkers are currently available to identify a risk-adapted strategy. We aim to investigate the role of circulating tumor DNA (ctDNA) and its clearance at different timepoints during chemo-radiotherapy (CRT) and correlate them with clinical outcomes. Between November 2014 and November 2019, we conducted a monocentric prospective observational study enrolling consecutive patients with LARC managed with neoadjuvant standard CRT (capecitabine and concomitant pelvic long-course radiotherapy), followed by consolidation capecitabine in selected cases and surgery. Blood samples for ctDNA were obtained at pre-planned timepoints. We evaluated the correlation of baseline variant allele frequency (VAF) with pathologic complete response (pCR) down-staging, node regression (pN0), event-free survival (EFS), and overall survival (OS). Among 112 screened patients, 61 were enrolled. In all, 38 (62%) had a positive ctDNA at baseline with VAF > 0 and 23 had negative ctDNA (VAF = 0). Among patients with negative ctDNA, 30% had a complete response, while only 13% of positive ctDNA patients had pCR [odds ratio (OR) 0.35 (95% confidence interval (CI): 0.10-1.26), p = 0.11]. Similarly, 96% and 74% of pN0 were observed among negative and positive ctDNA patients, respectively [OR 0.13 (95% CI: 0.02-1.07), p = 0.058]. The presence of a baseline VAF > 0 was associated with a trend toward a lower EFS compared with VAF = 0 patients [hazard ratio (HR) = 2.30, 95% CI: 0.63-8.36, p = 0.21]. Within the limitations of small sample size, no difference in OS was observed according to the baseline ctDNA status (HR = 1.18, 95% CI: 0.35-4.06, p = 0.79). Within the limitations of a reduced number of patients, patients with baseline negative ctDNA seem to show a higher probability of pN0 status and a trend toward improved EFS. Prospective translational studies are required to define the role of ctDNA analysis in the multimodal treatment of LARC.

Clinical particulars of acute coronary syndrome course in patients with COVID-19

Background: Cardiovascular complications of COVID-19 result in challenges for differential diagnosis, patients referral and treatment, which negatively affect the outcomes.&#x0D; Aim: To identify clinical particulars of various types acute coronary syndrome course in patients with COVID-19.&#x0D; Materials and methods: This retrospective cross-sectional study included 202 patients with COVID-19 and acute coronary syndrome (ACS) admitted to a primary vascular medicine center from September to December 2020. Their medical records were used for the analysis of ACS and COVID-19 clinical course, including physical and history data, laboratory and instrumental work-up. For the analysis, the patient sampling was divided into three study groups: 50 patients with unstable angina (UA), 107 patients with acute myocardial infarction with ST segment elevation (STEMI), and 45 patients with acute myocardial infarction without ST segment elevation (non-STEMI).&#x0D; Results: There were no differences in clinical manifestations of ACS in the study groups. As far as clinical manifestations of coronavirus infections are concerned, the patients differed significantly as per prevalence of fever and dry cough. Fever was present in 22 (44%) UA patients, 18 (17%) of STEMI patients and in 10 (22%) of non-STEMI patients (p 0.001 for comparison of 3 groups, Kruskall-Wallis test), whereas dry cough was present in 18 (36%), 19 (18%), and 14 (31%) patients, respectively (p = 0.029). Paired comparison (Mann-Whitney test with Bonferroni adjustment) showed significant differences between US and STEMI groups for both symptoms. The number of involved vessels (median [25%; 75%]) in UA patients was 0 [0; 2], in STEMI and non-STEMI patients 2 [1; 3] (p 0.001). A left coronary artery stenosis was detected in 2 (6%) of the UA patients, 13 (14%) of the STEMI and 4 (13%) of the non-STEMI patients (p = 0.452); left anterior descending artery stenosis, in 12 (36%), 67 (72%) and 23 (72%) patients, respectively (p 0.001). In the pairwise comparison, there were differences between UA and STEMI groups and between UA and non-STEMI groups. A left circumflex artery stenosis was found in 7 (21%) of the UA patients, 45 (48%) of the STEMI and 18 (56%) of the non-STEMI patients (p = 0.008); the pairwise comparisons showed the difference between UA and non-STEMI study groups. A right coronary artery stenosis was identified in 9 (27%), 64 (69%) and 18 (56%) of the study patients, respectively (p 0.001); in the pairwise comparison the difference was found between the UA and STEMI group. There were significant differences in the percentage of the right descendent and right coronary artery stenosis: the right descending artery stenosis was 70% [45; 80] in the UA patients, 90% [70; 100] in the STEMI and 95% [70; 100] in the non-STEMI patients (p = 0.013), whereas the right coronary artery stenosis was 50% [45; 80], 90% [70; 100], 90% [60; 100], respectively (p = 0.018). In the pairwise comparison, the differences were found between the UA and STEMI patients in both arteries. The STEMI patients had higher TIMI thrombus grade scores than those with non-STEMI: 3 [0; 5] vs 0 [0; 4] (p = 0.023). The rates of successful percutaneous coronary intervention and achievement of TIMI flow grade 3 between them was not significantly different (p = 0.170).&#x0D; Conclusion: The ACS patients with ACS and COVID-19 have high thrombotic load according to coronary angiography and TIMI score in the case of STEMI and more frequent absence of hemodynamically significant stenosis in those with UA and non-STEMI. The absence of any difference in clinical manifestations of ACS and viral infection between the study groups (except fever and dry cough difference between the UA and STEMI patients) indicates that specific characteristics of the ACS course in COVID-19 patients can be identified only by coronaroangiography.

Depression, cognitive dysfunction and other factors associated with 5-year overall mortality in type 2 diabetes mellitus: a pilot prospective observational study

BACKGROUND: Psychological predictors of overall mortality in the Russian population of Type 2 diabetic patients and their impact compared to biological risk factors have not been studied.AIM. To identify clinical, laboratory and psychological factors independently associated with the 5-year overall mortality in Type 2 diabetic patients in the Moscow region.MATERIALS AND METHODS: This open label observational prospective study included 178 consecutive type 2 diabetic patients (women 145, men 33, age range 37 to 82 years, duration of diabetes 0,5 to 30 years). At baseline, in addition to the standard clinical, laboratory and instrumental work-up, all patients were assessed for depression, cognitive dysfunction and diabetes-related quality of life. No study-related intervention was performed; all patients were followed up and treated by their local physicians. After 5 years, we assessed the patients’ vital status (alive or dead). Multiple logistic regression was used to identify baseline patients’ characteristics, which were significantly and independently associated with 5-year overall mortality. Taking into account the exploratory type of multiple regression, the results were considered significant at α&lt;0.1.RESULTS: At 5 years, 150 (84%) patients were alive and 15 (8,4%) were dead; no information could be obtained for the rest 13 (7,3%) patients. The analysis of 165 patients with the verified outcome, independent and significant associations with the death outcome were found for male gender (odds ratio [OR] 6,36 [95%CI 0,91–44.40]; p=0.06), age (OR 2.06 [1.30–3.27]; p&lt;0.002), chronic heart failure (CHF) (OR 2.78 [1.25–6.2]; р=0.012), Hamilton depression scale score (OR 1,18 [1.03–1.34]; р=0.016), cognitive dysfunction score (Roschina scale) (OR 1.20 [1.05–1.35]; р=0.006), and age — body mass index interaction (OR 0,98 [0,97–0,997]; р = 0,013). The predicted probability of death within the next 5 years in men and women was 22,9% and 6,7%, respectively. The highest score of cognitive dysfunction was associated with a 25% predicted probability of death and the lowest, with a 2% probability of death; predicted probabilities of death for the highest and lowest depression scores were 26% and 2%, respectively. The 5-year predicted probability of death in the patients without CHF was 6,7%, with CHF I NYHA functional class, 9,8%, II functional class 13,6%, III functional class 18,2%, and IV functional class 23,5%. All other baseline clinical, laboratory, demographic, psychological and socioeconomic variables were not significantly associated with the 5-year survival rate. The model was not verified on an external cohort.CONCLUSION: Cognitive dysfunction and depression have a significant negative impact on the 5-year mortality rate at much higher degree, than glycemic control, any diabetes-related complications and cardiovascular disorders, excluding CHF. The results obtained highlight the importance of the diagnosis and treatment of depression and cognitive dysfunction in type 2 diabetes mellitus.

A case of Graves' disease and type 1 diabetes mellitus following SARS-CoV-2 vaccination

Autoimmune diseases, including autoimmune endocrine diseases (AIED), are thought to develop following environmental exposure in patients with genetic predisposition. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and vaccines against it could represent new environmental triggers for AIED. We report a patient, with history of vitiligo vulgaris and 8 years of type 2 diabetes, who came to our institution because of fever, weight loss, asthenia and thyrotoxicosis occurred 4 weeks later the administration of BNT162B2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Clinical, biochemical and instrumental work-up demonstrated Graves’ disease and autoimmune diabetes mellitus. The occurrence of these disorders could be explained through different mechanism such as autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome), mRNA “self-adjuvant” effect, molecular mimicry between human and viral proteins and immune disruption from external stimuli. However further studies are needed to better understand the underlying pathogenesis of AIED following SARS-CoV-2 vaccine.

Venous thrombosis in patients after intracardial catheter interventions: incidence, risk factors, special aspects of the diagnosis

Rationale: Thrombosis of the puncture site in the femoral veins is one of the potentially dangerous complications of intracardial catheter interventions associated with thromboembolic risk related to its proximal location. According to the literature, the incidence of symptomatic venous thrombosis (VT) is 1–3%. No special studies on the assessment of risk factors for this complication, its diagnosis and treatment have been conducted.Aim: To study the incidence, risk factors and special aspects of VT diagnosis in patients undergoing intracardial electrophysiological studies (EFI) and/or catheter ablation.Materials and methods: This prospective study included 408 patients (194 men and 214 women, with median age of 51±10.1 years), who were admitted to the hospital with various cardiac rhythm disorders for intracardial EFIs and/or catheter ablations from 2016 to 2018. Before the interventions, in addition to common laboratory and instrumental work-up, all the patients underwent ultrasound duplex scanning (USDS) of the iliac-femoral segment; in 269 patients the level of D-dimer was measured. Latest at 24 hours after the intervention, all patients underwent a control ultrasound scan of the femoral vein puncture site. In case of VT occurrence anticoagulant therapy was started in all patients and they were followed up till complete VT resolution and at least for 3 months (the study endpoint). The VT incidence and its risk factors including the prognostic value of D-dimer levels were evaluated.Results: The VT incidence after catheter interventions was 11.7% (n=48). There was a significant correlation between VT occurrence and such risk factors as diabetes mellitus (p=0.001) and obesity (p&lt;0.001). No association between elevated baseline D-dimer values (&gt;500 ng/mL) and subsequent VT development was found (p&gt;0.05). The quartile analysis revealed an association between baseline D-dimer levels exceeding 434 ng/mL (which corresponds to the range of 75 to 100%) and the presence of the following risk factors: age over 65 years (p&lt;0.001), female gender (p=0.001), arterial hypertension (p=0.003), chronic coronary heart disease (p=0.044).Conclusion: In this study, all VTs (11.7%) detected after catheter transvenous interventions by USDS were asymptomatic. VTs were most frequent in patients with diabetes mellitus and obesity. D-dimer had no predictive value in the development of VT; however, its increased baseline values were more common in women, patients over 65 years, and in patients with arterial hypertension and chronic coronary heart disease.

Evaluation of an optimized [18 F]fluoro-deoxy-glucose positron emission tomography voxel-wise method to early support differential diagnosis in atypical Parkinsonian disorders.

Atypical Parkinsonian disorders (APD) frequently overlap in clinical presentations, making the differential diagnosis challenging in the early stages. The present study aimed to evaluate the accuracy of the [18 F]fluoro-deoxy-glucose positron emission tomography Statistical Parametric Mapping (SPM) optimized procedure in supporting the early and differential diagnosis of APD. Seventy patients with possible APD were retrospectively included from a large clinical cohort. The included patients underwent [18 F]fluoro-deoxy-glucose positron emission tomography within 3 months of the first clinical assessment and a diagnostic follow-up. An optimized SPM voxel-wise procedure was used to produce t-maps of brain hypometabolism in single subjects, which were classified by experts blinded to any clinical information. We compared the accuracy of both the first clinical diagnosis and the SPM t-map classifications with the diagnosis at follow-up as the reference standard. At first diagnosis, 60% of patients were classified as possible APD (progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy) and about 40% as APD with uncertain diagnosis, providing 52% sensitivity, 97% specificity and 86% accuracy with respect to the reference standard. SPM t-map classification showed 98% sensitivity, 99% specificity and 99% accuracy, and a significant agreement with the diagnosis at follow-up (P < 0.001). The SPM t-map classification at entry predicted the second diagnosis at follow-up. This indicates its significantly superior role for an early identification of APD subtypes, particularly in cases of uncertain diagnosis. The use of a metabolic biomarker at entry in the instrumental work-up of APD may shorten the diagnostic time, producing benefits for treatment options and support to the patients.

Diagnostic and therapeutic errors in cluster headache: a hospital-based study.

BackgroundCluster headache (CH) is a severe, disabling form of headache. Even though CH has a typical clinical picture it seems that its diagnosis is often missed or delayed in clinical practice. CH patients may thus face: misdiagnosis, unnecessary investigations and delays in accessing adequate treatment. This study was conducted to investigate the occurrence of diagnostic and therapeutic errors with a view to improving the clinical and instrumental work-up in affected patients.MethodsOur study comprised 144 episodic CH patients: 116 from Italy and 28 from Eastern European countries (Moldova, Ukraine, Bulgaria). One hundred six patients (73.6%) were examined personally and 38 (26.4%) were evaluated through telephone interviews conducted by headache specialists using an ad hoc questionnaire developed by the authors.ResultsThe sample was predominantly male (M:F ratio 2.79:1) and had a mean age of 42.4 ± 9.8 years; approximately 76% of the patients had already consulted a physician about their CH at the onset of the disease. The mean interval between onset of the disease and first consultation at a headache center was 4.1 ± 5.6 years. The patients had consulted different specialists prior to receiving their CH diagnosis: neurologists (49%), primary care physicians (35%), ENT specialists (10%), dentists (3%), etc. Misdiagnoses at first consultation were recorded in 77% of the cases: trigeminal neuralgia (22%), migraine without aura (19%), sinusitis (15%), etc. The average “diagnostic delay” was 5.3 ± 6.4 years and the condition was diagnosed approximately (“doctor delay”: one year). Instrumental and laboratory investigations were carried out in 93% of the patients prior to diagnosis of CH. Some of the patients had never received abortive or preventive medications, either before or after diagnosis. Medical prescription compliance: 88% of the cases.ConclusionsOur results emphasize the need to improve specialist education in this field in order to improve recognition of the clinical picture of CH and increase knowledge of the proper medical treatments for de novo CH. Continuous medical education on CH should target general neurologists, primary care physicians, ENT specialists and dentists. A study on a larger population of CH patients may further improve error-avoidance strategies.

Myocardial Fibrosis as a Key Determinant of Left Ventricular Remodeling in Idiopathic Dilated Cardiomyopathy

Background— In idiopathic dilated cardiomyopathy, there are scarce data on the influence of late gadolinium enhancement (LGE) assessed by cardiovascular magnetic resonance on left ventricular (LV) remodeling. Methods and Results— Fifty-eight consecutive patients with idiopathic dilated cardiomyopathy underwent baseline clinical, biohumoral, and instrumental workup. Medical therapy was optimized after study enrollment. Cardiovascular magnetic resonance was used to assess ventricular volumes, function, and LGE extent at baseline and 24-month follow-up. LV reverse remodeling (RR) was defined as an increase in LV ejection fraction ≥10 U, combined with a decrease in LV end-diastolic volume ≥10% at follow-up. ΔLGE extent was the difference in LGE extent between follow-up and baseline. LV-RR was observed in 22 patients (38%). Multivariate regression analysis showed that the absence of LGE at baseline cardiovascular magnetic resonance was a strong predictor of LV-RR (odds ratio, 10.857 [95% confidence interval, 1.844–63.911]; P =0.008) after correction for age, heart rate, New York Heart Association class, LV volumes, and LV and right ventricular ejection fractions. All patients with baseline LGE (n=26; 45%) demonstrated LGE at follow-up, and no patient without baseline LGE developed LGE at follow-up. In LGE-positive patients, there was an increase in LGE extent over time ( P =0.034), which was inversely related to LV ejection fraction variation (Spearman ρ, −0.440; P =0.041). Five patients showed an increase in LGE extent &gt;75th percentile of ΔLGE extent, and among these none experienced LV-RR and 4 had a decrease in LV ejection fraction ≥10 U at follow-up. Conclusions— In patients with idiopathic dilated cardiomyopathy, the absence of LGE at baseline is a strong independent predictor of LV-RR at 2-year follow-up, irrespective of the initial clinical status and the severity of ventricular dilatation and dysfunction. The increase in LGE extent during follow-up was associated with progressive LV dysfunction.

The coloboma of the choroid simulating optic nerve duplication

In the article, a coloboma of the choroid is described simulating optic disc duplicaton as well as modern possibilities of instrumental work-up methods, which allowed to make a diagnosis. A coloboma (from the Greek koloboma, meaning defect) — is a defect of lid tissues, iris, choroid or optic nerve. A coloboma may be сongenital or acquired. A typical coloboma of the choroid is localized in the lower part of the eye fundus. At times, it comes down to the optic disc, and sometimes involves it as well. The white color of the defect is due to the show-through of the sclera, because the choroid here is completely absent. Corresponding to the coloboma of the choroid, the retina is hypoplastic or absent at times. An optic disc duplication — at this anomaly there are two optic discs on the eye fundus. Sometimes, both may be phtitical and hypoplastic, but more often one of them is hypoplastic, and the second one is performing its function. A true optic disc duplication comes out of the optic nerve partition into 2 or more fascicles. The duplicated optic nerve is pointed out by two optic foramens in one orbit by radiographic analysis, two blind spots in the visual field of one eye, simultaneous central retinal artery pulsation on both optic discs. Ultrasonic B-scanning or OCT and MRI may confirm the existence of a true optic nerve and optic disc duplication. A pseudo-duplication of the optic disc is also very rare and represents a well delineated defect, close to the normal optic disc and simulating an ancillary optic disc with an adjoining area of chorioretinal atrophy.

Feasibility of the Laparoscopic Total Colectomy with Ileal j-Pouch-Rectal Anastomosis in the Treatment of Chronic Constipation Refractory to Medical Therapy: Observations about a Case Report

In October 2012, a 29-year-old woman affected by chronic constipation underwent surgery for a laparoscopic total colectomy with ileal j-pouch-rectal anastomosis. After a precise instrumental work-up, the patient was selected as a potential candidate for the surgical treatment after failing to respond to all other medical treatment. During the first three months following the surgery, the patient recorded 3 - 4 daily evacuations of soft stool. After the third month, the number of evacuations stabilised at 2 - 3 a day, with formed stool, and no mention of incontinence or abdominal pain. Although the laparoscopic total colectomy with ileorectal anastomosis (TC with IRA) and the laparoscopically assisted subtotal colectomy with cecorectal anastomosis (SC with CRA) are the most frequently practiced procedures in the surgical treatment of chronic constipation, the laparoscopic colectomy with ileal j-pouch has shown in our experience to be a feasible and effective procedure, with similar results to the two aforementioned procedures in terms of morbidity, mortality and quality of life. In fact, like the first two, the total colectomy with ileal j-pouch has demonstrated the advantages of laparoscopic surgery: low invasiveness, less post-operative pain or ileus, respect of parietal integrity, reduced hospitalization and, lastly, a better cosmesis.

Genetic-clinical profile of subjects with apparently sporadic extra-adrenal paragangliomas

Background: Mutations in the genes encoding B, C, and D subunits of the succinate dehydrogenase (SDH) are involved in the pathogenesis of familial paraganglioma (PGL) syndrome. Many subjects with apparently sporadic extra-adrenal paragangliomas are found to be carrier for SDH mutation. Objective: Here we describe four subjects with apparently sporadic extra-adrenal paragangliomas with newly identified mutations in the SDH subunit B and the related clinical phenotype. Methods: Gene sequencing was performed to search for mutations in the SDHB (all exons), SDHC (all exons), and SDHD (all exons) genes as well as VHL (all exons) and RET (10, 11, 13, 14, 15, 16 exons) genes in all four index cases. A complete clinical, biochemical, and instrumental work-up was performed. Results: Three subjects were found to be affected with a nonsense SDHB germline mutation (Q30X, Y61X, and W201X, respectively). These mutations are predicted to encode for a truncated SDHB protein. The fourth subject presented a S195del frameshift mutation, causing a deletion of the codon AGC, encoding for a serine. Clinical presentation and course of each patient is described. Conclusions: Extra-adrenal paragangliomas, localized in the sympathetic ganglia (in the posterior thorax or in the abdomen), are very often SDHB-inherited form rather than sporadic tumor. Our data confirm the importance of genetic screening in patients affected with paragangliomas and enlarge the list of mutations responsible for the presence of these tumors.

Phenotypic Heterogeneity of the GRN Asp22fs Mutation in a Large Italian Kindred

The Asp22fs(g.63_64insC) mutation in progranulin gene (GRN) has been so far reported in one patient who developed frontotemporal dementia (FTD) at the age of 65. Here, we describe the clinical heterogeneity associated with the GRN Asp22fs mutation in a large Italian family. Clinical and instrumental workup of two symptomatic carriers in two generations has been carried out, together with genetic analysis of probands and of nine asymptomatic family members. The first proband was a 47-year old male clinically diagnosed with FTD. Family history was positive and suggestive of an autosomal dominant pattern of inheritance. Evaluation of plasma GRN levels was consistent with the presence of a mutation in its encoding gene, that was demonstrated by sequencing [Asp22fs(g.63_64insC)]. Brain MRI showed multiple T2 and FLAIR hyperintense areas in the frontal lobe white matter and right hemisphere cortical atrophy. The second proband was his 79 year old uncle, presenting with mild cognitive impairment. Brain MRI showed small T2 hyperintense lesions and widespread cortical atrophy. Cerebrospinal fluid amyloid-β, tau, and phosphotau protein levels were in both cases in the range of normality. Additional nine asymptomatic family members were studied. This family's description expands the spectrum of clinical presentations of frontotemporal lobar degeneration caused by GRN mutations, suggesting that the diagnosis could be missed in some individuals with an atypical presentation, and points up the importance of GRN plasma level evaluation.

Primary Cytomegalovirus Infection in Otherwise Healthy Adults with Fever of Unknown Origin: A 3-Year Prospective Survey

Primary cytomegalovirus disease is probably still underestimated or missed in common clinical practice, and further prevalence studies should be performed, in particular in the setting of fever of under-determined origin (FUO) in adults. In a 3-year prospective survey of 123 consecutive adult patients referred for FUO often associated with a broad spectrum of constitutional signs and symptoms, 18 patients (14.6%) were found to have a primary cytomegalovirus infection, after a clinical, instrumental and laboratory workup. In the majority of cases, this syndrome was consistently associated with altered white blood cell count, abnormal T-lymphocyte subsets and ultrasonography-confirmed hepatosplenomegaly. On the other hand, altered white blood cell differential and serum hepatic enzymes, and constitutional signs and symptoms were absent in 11.1-27.8% of cases, and an initial laboratory cross-reaction with anti-Epstein-Barr IgM antibodies was detected in 44.4% of episodes. Non-specific signs and symptoms were the only features in 27.8% of patients with adult cytomegalovirus disease, thus, confirming that this disorder may be still clinically underestimated, until virologic assays are performed. A prolonged and varied spectrum of subjective disturbances (similar to those encountered in infectious mononucleosis), which often limited daily activities, involved nearly 30% of subjects, and lasted for 3-15 months after recovery of acute cytomegalovirus disease. In the clinical, laboratory, and instrumental workup for FUO, rapid recognition of a primary cytomegalovirus disease is useful to exclude alternative diagnoses, avoid non-necessary exposure to antibiotics, and reassure patients of their self-limiting, benign disorder.

Different responses to chronic somatostatin analogues in patients with central hyperthyroidism

Central hyperthyroidism is mainly due to two different causes, TSH-secreting pituitary adenoma (TSH-oma) and resistance to thyroid hormone in its pituitary variant, i.e. patients presenting with signs and symptoms of hyperthyroidism (PRTH). Because therapeutic approach and the clinical follow-up are extremely different in these two disorders, a correct differential diagnosis is mandatory. Unfortunately, no definite pathognomonic tool is presently available and an extensive biochemical and instrumental workup is frequently needed in order to reach the correct diagnosis. Aim of the present study was to investigate the use of somatostatin analogues in the differential diagnosis between TSH-omas and PRTH, as well as the possible treatment of PRTH with these analogues. Eight patients with TSH-oma and four with PRTH underwent the acute test with somatostatin analogue Octreotide (0.1 mg subcutaneously), as well as long-acting Octreotide-LAR (30 mg intramuscularly every 28 days) for two months. Serum TSH, FT3 and FT4 were evaluated in basal condition, at time 0 and every hour for 6 h during acute test, and every 15 days for 2 months during chronic treatment. During acute test, in both patients with PRTH and TSH-oma, a similar reduction in immunoreactive TSH and FT3 levels was observed, while no variations were found in FT4 concentrations. In contrast, during the administration of Octreotide-LAR, no significant variations of all tested parameters were observed in PRTH group, whereas FT3 and FT4 concentrations normalized or presented a significant reduction (> 30% of pretreatment values) in seven of eight patients with TSH-oma, despite minor variation of immunoreactive TSH levels. Chronic administration of long-acting somatostatin analogues in patients with central hyperthyroidism caused a marked decrease of FT3 and FT4 levels in all patients but one with TSH-oma, while patients with PRTH did not respond at all. Thus, administration of long acting somatostatin analogues for at least 2 months can be useful in the differential diagnosis in problematic cases of central hyperthyroidism. Furthermore, the present findings exclude the possibility of a beneficial effect of chronic administration of somatostatin analogues in controlling thyrotoxic symptoms in PRTH patients.

Internal Borderzone Infarction in Patients with Ischemic Stroke

Objective: The mechanism underlying cerebral infarction in the borderzone between the territories of deep and superficial perforating arteries has not yet been clarified. This study was performed to investigate the prevalence, volume, site, and etiology of this type of subcortical infarction in a large unselected group of stroke patients. Methods and Patients: We analyzed a continuous series of 383 patients with recent cerebral infarction observed in our Stroke Unit. Patients underwent a complete clinical and instrumental workup. The subgroup of subjects with internal borderzone infarct alone were compared with the subgroups of patients with other types of cerebral infarcts by uni- and multivariate statistical tests. Results: There were 90 internal borderzone infarcts of 725 ischemic lesions (12% of the total), with a median volume of 0.32 ml (95% confidence interval 0.24–0.44; range: 0.012–20.2 ml). Internal borderzone infarcts alone occurred in only 13 of 383 (3.4%) patients. A comparison between patients with ‘pure’ internal borderzone infarction and patients with other types of cerebral infarcts by multiple logistic regression analysis demonstrated a significant independent causal role of carotid stenosis or occlusion. Conclusion: Our study suggests that ‘pure’ internal borderzone infarctions are quite rare findings in patients with ischemic stroke, and that the hemodynamic impairment due to atherosclerotic occlusion or stenosis of the carotid system could be the cause in the large majority of cases.