Epidemiology of sepsis in Internal Medicine Units of Apulia: results of SEMINA (SEpsis Management in INternal medicine Apulia) study.

Background: The prevalence and mortality of sepsis in Internal Medicine Units (IMUs) is poorly understood as most of the data derive from studies conducted in Intensive Care Units. Aim of SEpsis Management in INternal medicine Apulia (SEMINA) study was to determine the prevalence of sepsis and the characteristics and outcomes of patients with Sepsis-3 criteria admitted in Apulia's Internal Medicine Units for over six months. Methods: The SEpsis Management in INternal medicine of Apulia study was a prospective, multicentre, observational study. Adult admissions to the 13 Apulia Region's Internal Medicine Units between November 15, 2018 and May 15, 2019 were screened for sepsis according to the Sepsis-3 criteria. Medical data were collected in electronic case report form. Results: Out of 7,885 adult patients of the Internal Medicine Units, 359 (4.55%) fulfilled the inclusion criteria, and 65 of them (18.1%) met the septic shock criteria. The patients enrolled were elderly, suffering from chronic poly-pathologies and from cognitive and functional impairment. The respiratory system was the most common site of infection and the most common pathogens isolated from blood cultures were Staphylococcus spp., E. coli, Klebsiella spp., Enterococcus spp. and Acinetobacter spp. The in-hospital fatality rate was 31.2% and was significantly higher for septic shock. Sequential Organ Failure Assessment score, dementia and infections from Acinetobacter spp. were independent risk factors for mortality. Conclusions: A high prevalence of sepsis and a high fatality rate were detected in Apulia Region's Internal Medicine Units. The high fatality rate observed in our study could be related to the underlying diseases and to the vulnerability of elderly patients admitted to our Internal Medicine Units.

Management of diabetes in older adults.

Type 2 diabetes prevalence is high in older adults and is expected to rise in the next decades. Diabetes in the population of frail older adults is accompanied by functional disability, several comorbidities, and premature mortality. A comprehensive geriatric assessment, including functional, cognitive, mental and social status, is advisable for identifying the glycemic targets and glucose-lowering therapies, focused on patient preferences, needs, and risks. The therapeutic options for older adults with diabetes are like those for the adult population. However, the pharmacological treatments must be carefully prescribed and monitored, taking into consideration the patient cognitive capacities, the potentially life-threatening drug-drug interactions, the cardiovascular risk, and with the main goal of avoiding hypoglycemia. Also, a careful nutritional evaluation with appropriate tools, as well as a balanced and periodically monitored physical activity, contribute to an effective tailored care plan, as needed by older adults with diabetes. This review evaluates the currently available hypoglycemic drugs and the current indications to the Italian diabetology community, specifically with regard to the treatment of adults aged 75 years or older with diabetes, including the unmet needs by the guidelines.

The impact of interferon lambda 3 gene polymorphism on natural course and treatment of hepatitis C.

Host genetic factors may predict the outcome and treatment response in hepatitis C virus (HCV) infection. Very recently, three landmark genome-wide association studies identified single nucleotide polymorphisms near the interleukin 28B (IL28B) region which were more frequent in responders to treatment. IL28B encodes interferon (IFN)λ3, a type III IFN involved in host antiviral immunity. Favourable variants of the two most widely studied IL28B polymorphisms, rs12979860 and rs8099917, are strong pretreatment predictors of early viral clearance and sustained viral response in patients with genotype 1 HCV infection. Further investigations have implicated IL28B in the development of chronic HCV infection versus spontaneous resolution of acute infection and suggest that IL28B may be a key factor involved in host immunity against HCV. This paper presents an overview about the biological activity and clinical applications of IL28B, summarizing the available data on its impact on HCV infection. Moreover, the potential usefulness of IFNλ in the treatment and natural history of this disease is also discussed.

Change of γδTCR-expressing T cells in healthy aging.

A mature T-cell lineage with the capacity to proliferate in response to receptor-mediated signals and to display non-major histocompatibility complex (MHC)-restricted cytolysis expresses a CD3-associated heterodimer made up of the protein encoded by the T-cell receptor (TCR) gamma-gene. We investigated the possible differences in lymphocyte subpopulations between healthy young-middle-aged and elderly subjects, focusing attention on γδ-TCR-expressing cells. The study was carried out on fifteen healthy young-middle-aged male subjects (age range 36-55 years) and fifteen healthy elderly male subjects (age range 67-79 years). Lymphocyte subpopulations were analyzed in blood samples collected every four hours for 24 hours. The presence of circadian rhythmicity on absolute counts was validated to evaluate the periodicity of variation, and the fractional variation between single time point values was calculated to evaluate the dynamics of variation. In the group of young and middle-aged subjects a clear circadian rhythm was validated for the time-qualified changes of all the lymphocyte subpopulations (CD3, CD4, CD4/CD8 ratio, CD20, CD25 and HLA-DR with acrophase at night, CD8, CD16 and TcR γδ with acrophase at noon). In the group of elderly subjects a clear circadian rhythm was validated for the nyctohemeral changes of CD3, CD8, CD4/CD8 ratio, CD16, CD25. There was a statistically significant difference for the Midline Estimating Statistic of Rhythm (MESOR) of CD3 (p=0.001), CD25 (p=0.003) and γδ-TCR-expressing cells (p=0.004), higher in the elderly, and for the MESOR of HLA-DR (p=0.002) and CD20 (p=0.002) higher in the young and middle-aged subjects. There was a statistically significant difference between the groups in the fractional variation of TcR γδ-expressing cells between 18:00h and 22:00h values (higher in elderly subjects, p=0.007). In conclusion, specific lymphocyte subsets present different levels and different profiles of nyctohemeral changes in healthy young-middle aged in respect to elderly subjects, since B cells are decreased, whereas CD25 and γδ -TCR-bearing cells are higher in the elderly, but the rhythm and the dynamics of variation of this lymphocyte subset is severely altered and this phenomenon might contribute to the onset of age-related variations of the immune responses.

Arterial endothelial dysfunction and idiopathic deep venous thrombosis.

Recent epidemiological studies have highlighted higher risk of subsequent development of atherosclerotic disease in patients with deep venous thrombosis (DVT). We evaluated the Flow Mediated Dilation (FMD) looking for arterial endothelial dysfunction, predictive for future ischaemic cardiovascular events, in patients with idiopathic DVT. FMD was measured in the brachial artery in 60 subjects with idiopathic DVT (age 60.1±17.4) and in 60 subjects without idiopathic DVT (age 61.2±15.1), with a similar cardiovascular risk factor profile. DVT patients showed lower FMD (6.78%±5.53% vs 10.88±3.31%, p<0.001). Univariate linear models showed that obesity (p=0.010), dyslipidemia (p=0.004), arterial hypertension (p=0.046), use of platelet anti-aggregating agents (p=0.018) and DVT (p<0.001) were associated to lower levels of FMD. In multivariate linear model, only DVT (p<0.001) remained an independent predictor of lower levels of FMD. Furthermore, an 8.5% cut-off value of FMD was chosen in a ROC curve analysis. Values of FMD ≤ 8.5% were more frequent in DVT patients (71.67% vs 41.67%, p<0.001). Univariate logistic regression models showed that dyslipidemia (p=0.008), use of platelet anti-aggregating agents (p=0.004) and DVT (p<0.001) were associated to a higher risk of having FMD ≤ 8.5%. Multivariate logistic regression model showed that DVT was the unique independent predictor for FMD ≤ 8.5% (p<0.001). In conclusion, DVT patients more frequently have impaired FMD, recognized as an indicator of arterial endothelial dysfunction and a marker for increased cardiovascular risk.

Ultrasound-guided fine needle aspiration biopsy (FNAB) demonstrating upper distal extremity metastasis of lung adenocarcinoma: a case report and review of the literature.

Due to early metastasis and delayed diagnosis, lung cancer is the leading cause of cancer-related deaths. Although the most common metastasis sites are brain, bone, lung, adrenal glands, liver, and extra-thoracic lymph node, soft tissues, such as skeletal muscles, skin, and subcutaneous tissues, can also be undermined. This article aims to report the first case of an asymptomatic radial extensor muscle metastasis generating from a lung adenocarcinoma that was diagnosed by ultrasound-guided fine-needle aspiration biopsy (FNAB).

Immunopathogenetic and pharmacological aspects of interstitial lung diseases.

Interstitial lung diseases (ILDs) are inflammatory diseases characterized by slow and progressive destruction of alveolar-capillary functional units, often leading to respiratory failure and death. A first stage of alveolitis and a following stage of fibrosis provoke an anatomical distortion of the peripheral airways and the interstitium, and for their smoldering evolution and non-specificity of symptoms ILDs may remain undiagnosed and untreated for a long time. In this review we exploited the immunopathogenetic aspects and the therapeutical approaches to this frequently unrecognized and severe disease.

Circadian variations of cortisol, melatonin and lymphocyte subpopulations in geriatric age.

A number of age-related changes in the 24-hour hormonal and non-hormonal rhythms have been found in older human beings. Lymphocyte subpopulations present circadian variation of some of their subsets and this variation may influence magnitude and expression of the immune responses. Numerous interactions exist among the nervous, endocrine and immune systems, mediated by neurotransmitters, hormones and cytokines. The aim of this study is to evaluate circadian variations of some endocrine and immune factors in older adults. Cortisol and melatonin serum levels were measured and lymphocyte subpopulation analyses were performed on blood samples collected every four hours for 24 hours from ten healthy young and middle-aged subjects and from ten healthy elderly subjects. There was a statistically significant difference between the groups in the observed values of CD20 (higher in young and middle-aged subjects) and CD25 and DR+ T cells (higher in elderly subjects). In the group of young and middle-aged subjects a clear circadian rhythm was validated for the time-qualified changes of all the factors studied. In the group of elderly subjects a number of rhythms were absent or altered. The results of the current study show that aging is associated with enhanced responsiveness of T cell compartment and alterations of circadian rhythmicity.

Impact of Nutritional Status on Muscle Architecture in Elerly Patients Hospitalized in Internal Medicine Wards.

Nutritional alterations are highly prevalent in older rather than adult hospitalized patients. In these subjects, a loss of physical performance is dependent on the impairment of muscle architecture. This study aimed to investigate the association between the nutritional status and muscle architecture in elderly patients hospitalized in internal medicine wards. 68 aged patients admitted in internal medicine wards were consecutively enrolled and stratified in three groups based on the Mini Nutritional Assessment (MNA) score: well-fed (WF), at risk of malnutrition (RM), and malnourished (M). Biochemical indices and anthropometric parameters were sampled at hospital admission. Furthermore, all patients were assessed at admission and after 7 days of hospitalization for muscle strength (hand-grip test), mass (bioimpedentiometry), and architecture (ultrasonography of vastus lateralis). At hospital admission, M patients showed lower percentage of fat free mass and muscle mass with respect to WF and RM. Furthermore, M group presented with lower muscle thickness and pennation angle, as compared to WF and RM. At admission, the MNA score was positively related to the pennation angle and muscle strength. Multivariate linear regression analysis showed that the nutritional status at admission was the only significant factor influencing pennation angle. Finally, during the first 7 days of hospitalization, a decrease of pennation angle occurred in all the groups studied. We conclude that malnutrition at admission is associated with impaired muscle architecture in elderly patients hospitalized in internal medicine wards. Moreover, muscle architecture is impacted by early hospitalization, irrespective of nutritional status.

Venous thromboembolism during mycoplasma pneumoniae infection: case report and review of the literature.

Mycoplasma pneumoniae infection is frequent but generally mild or self-limiting. Approximately 10% of cases develop clinical signs of pneumonia with "atypical" radiographic pattern. However, mycoplasma pneumoniae can be responsible for a variety of extrapulmonary manifestations, potentially involving all systems and apparatuses. Although exact pathophysiological mechanisms are not completely known, these could be secondary to direct invasion of the target organ, immunological damage due to molecular mimicry or vascular obstruction. A 45-year-old man was admitted to Internal Medicine Unit because of fever, dry cough and fatigue lasting 15 days. Fever disappeared after starting clarithromycin. About 72 h after admission the patient complained of right calf pain and tachypnea. The presence of anti-mycoplasma antibodies suggested mycoplasma pneumoniae infection. Moreover, a diagnosis of venous thrombo-embolism was performed. Given the absence of classical risk factors for thrombosis, patient was investigated for inherited and acquired thrombophilia and tested positive for antiphospholipid antibodies. A review of the English literature on the association between m. pneumoniae and pulmonary embolism will be provided in order to underline the possible pathogenetic role of antiphospholipid antibodies in this setting. Clinicians should outweigh risk and benefits for LMWH prophylaxis case by case considering these adjunctive pro-thrombotic mechanisms in patients m. pneumoniae infection.

Reduced glomerular filtration rate and prior cardiovascular event entail similar risk for coronary atherosclerotic burden.

OBJECTIVE: Prior cardiovascular event and kidney dysfunction are both strong risk factors for coronary artery disease. The aim of this study is to assess coronary atherosclerotic burden in a large population of patients undergoing coronary angiography, according to prior cardiovascular event or chronic kidney disease. PATIENTS AND METHODS: We evaluated 700 consecutive patients who underwent coronary angiography (CA). Serum creatinine to estimate glomerular filtration rate (eGFR) was measured. Clinically significant coronary artery disease (CAD) was defined by the presence of a coronary lesion resulting in a luminal stenosis >50%. For the purpose of the study, the whole population was divided into 4 subgroups according to the presence/absence of eGFR <60 ml/min/1.73 m2 or prior cardiovascular event: eGFR≥60/no event (Group A), eGFR≥60/yes event (Group B), eGFR<60/no event (Group C), eGFR<60/yes event (Group D). PATIENTS: As expected, patients in group D had the worst clinical and biochemical profile. These patients also presented the highest values of urinary albumin creatinine ratio (ACR, p<0.001) and the lowest values of eGFR (p<0.01). One-hundred-ninety-six patients had three-vessel disease. Patients who had undergone PCI procedure showed a lower eGFR as compared to patients who had not (p=0.009). Considering group A as reference, the risk of having three-vessel disease was increased in group B (OR= 2.09; 95% CI 1.37-3.19), in group C, (OR= 1.80; 95% CI 1.04-3.14), and finally in group D (OR= 3.35; 95% CI 2.01-5.58). The risk carried by group C was not significantly different from that carried by Group B: OR= 0.86; 95% CI 0.5-1.5. CONCLUSIONS: In our study, low eGFR seems to have the same excess risk of prior CV event.

Frailty syndrome is associated with altered circulating redox balance and increased markers of oxidative stress.

Frailty syndrome (FS) is a condition described in aging and characterized by physical vulnerability to stress and lack of physiological reserve. In this study we aim to define whether circulating oxidative stress correlates to frailty in terms of glutathione balance and oxidative protein damage. In 62 elderly outpatients, classified as frail patients according to Fried's criteria, evaluation of reduced glutathione (GSH), oxidized glutathione (GSSG), tumor necrosis factor-alpha, malonaldehyde-(MDA) and 4-hydroxy-2,3-nonenal-(HNE) protein plasma adducts were performed. A significant increase in the GSSG was observed in patients with FS when compared to non-frail. No difference was shown in the GSH amount, suggesting a glutathione oxidation more than impairment of the synthesis. TNF-alpha, MDA- and HNE-adducts, were significantly higher in FS as compared to non-frail patients. A logistic regression model correlating FS with redox balance showed a close relationship between glutathione ratio (OR=1.8, 95% CI=1.2-2.5) and MDA adducts (OR=2.8, 95% CI=1.6-4.7) to frailty. Our findings show an association between oxidative imbalance and Frailty Syndrome. GSSG/GSH ratio and plasma protein adducts strongly predict the frailty conditions and seem to be reliable and easily measurable markers in the context of the multidimensional analysis of elderly patients.

Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury.

BACKGROUND: The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Mitochondrial dysfunction represents a key factor in the progression of non-alcoholic steatohepatitis (NASH) as mitochondria are the main cellular site of fatty acid oxidation, ATP synthesis and reactive oxygen species (ROS) production. AIMS: (1) To evaluate the role of the uncoupling protein 2 in controlling mitochondrial proton leak and ROS production in NASH rats and humans; and (2) to assess the acute liver damage induced by ischaemia-reperfusion in rats with NASH. METHODS: Mitochondria were extracted from the livers of NASH humans and rats fed a methionine and choline deficient diet. Proton leak, H(2)O(2) synthesis, reduced glutathione/oxidised glutathione, 4-hydroxy-2-nonenal (HNE)-protein adducts, uncoupling protein-2 (UCP2) expression and ATP homeostasis were evaluated before and after ischaemia-reperfusion injury. RESULTS: NASH mitochondria exhibited an increased rate of proton leak due to upregulation of UCP2. These results correlated with increased production of mitochondrial hydrogen peroxide and HNE-protein adducts, and decreased hepatic ATP content that was not dependent on mitochondrial ATPase dysfunction. The application of an ischaemia-reperfusion protocol to these livers strongly depleted hepatic ATP stores, significantly increased mitochondrial ROS production and impaired ATPase activity. Livers from patients with NASH exhibited UCP2 over-expression and mitochondrial oxidative stress. CONCLUSIONS: Upregulation of UCP2 in human and rat NASH liver induces mitochondrial uncoupling, lowers the redox pressure on the mitochondrial respiratory chain and acts as a protective mechanism against damage progression but compromises the liver capacity to respond to additional acute energy demands, such as ischaemia-reperfusion. These findings suggest that UCP2-dependent mitochondria uncoupling is an important factor underlying events leading to NASH and cirrhosis.

Alterations of hepatic ATP homeostasis and respiratory chain during development of non-alcoholic steatohepatitis in a rodent model.

BACKGROUND: Mitochondrial dysfunction is considered a key player in non-alcoholic steatohepatitis (NASH) but no data are available on the mitochondrial function and ATP homeostasis in the liver during NASH progression. In the present paper we evaluated the hepatic mitochondrial respiratory chain activity and ATP synthesis in a rodent model of NASH development. MATERIALS AND METHODS: Male Wistar rats fed a High Fat/Methionine-Choline Deficient (MCD) diet to induce NASH or a control diet (SHAM), and sacrificed after 3, 7 and 11 weeks. The oxidative phosphorylation, the F(0)F(1)ATPase (ATP synthase) and the ATP content were assessed in liver mitochondria. RESULTS: NASH mitochondria exhibited an increased rate of substrate oxidation at 3 weeks, which returned to below the normal level at 7 and 11 weeks, concomitantly with the coupling between the phosphorylation activity and the mitochondrial respiration (ADP/O). Uncoupling of NASH liver mitochondria did not allow the recovery of the maximal respiration rate at 7 and 11 weeks. The ATPase (ATP synthase) activity was similar in NASH and SHAM rats, but the mitochondrial ATP content was significantly lower in NASH livers. CONCLUSIONS: The loss of hepatic ATP stores is not dependent on the F(0)F(1)-ATPase but resides in the respiratory chain. Dysfunction of both Complex I and II of the mitochondrial respiratory chain during NASH development implies a mitochondrial adaptive mechanism occurring in the early stages of NASH.

Vascular risk factors, alcohol intake, and cognitive decline.

Since the therapeutic options currently available have demonstrated limited efficacy, the search for preventive strategies for cognitive decline and dementia is mandatory. A possible role of vascular and lifestyle-related factors was recently proposed for age-related changes of cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin. At present, cumulative evidence suggested that vascular risk factors may be important in the development of mild cognitive impairment (MCI), dementia, and AD. Among vascular-related factors, metabolic syndrome has been associated with the risk of cognitive decline and overall dementia. Moderate alcohol drinking has been proposed as a protective factor against MCI and dementia in several longitudinal studies, but contrasting findings also exist. However, in most cases, these were only observational studies, and results are awaited from large multicenter randomized clinical trials in older persons. At present, vascular risk factor management, lifestyle changes, and drugs could be employed together to delay the onset of dementia syndromes.

Dietary fatty acids, age-related cognitive decline, and mild cognitive impairment.

Currently available epidemiological evidence suggested that an increase of saturated fatty acids (SFA) could have negative effects on cognitive functions, while increased polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA) may be protective against cognitive decline. In a Southern Italian elderly population from the Italian Longitudinal Study on Aging (ILSA), a clear reduction of risk of age-related cognitive decline (ARCD) has been found with elevated intake of PUFA and MUFA. Furthermore, in the ILSA, while dietary fatty acids intakes were not associated with incident mild cognitive impairment (MCI), high PUFA intake appeared to have borderline non-significant trend for a protective effect against the development of MCI. These epidemiological findings on predementia syndromes, i.e. MCI or ARCD, together with a recent randomised controlled trial on a possible effect on cognitive and depressive symptoms of omega-3 PUFA supplementation in patients with very mild AD, suggested a possible role of fatty acids intake in maintaining adequate cognitive functioning and possibly in preventing or delaying the onset of dementia.

Paradoxical embolism with thrombus stuck in a patent foramen ovale: a review of treatment strategies.

OBJECTIVE: Paradoxical embolism represents a rare condition occurring when a thrombus originating from venous system produces pulmonary embolism and systemic embolization through an intracardiac or pulmonary shunt. The evidence of a thrombus entrapped in a patent foramen ovale (PFO) is an even more rare condition. There is uncertainty about the optimal treatment strategy. PATIENTS AND METHODS: A 58-year-old male patient was admitted to our Internal Medicine Unit with the diagnosis of bilateral bronchopneumonia. During hospitalization, the co-occurrence of chest pain and amaurosis led us to hypothesize a paradoxical embolism. RESULTS: Transthoracic echocardiography showed the presence of a thrombus stuck over the interatrial septum. A contrast-enhanced chest CT scan showed multiple pulmonary embolisms and brain CT scan documented a hypodense area, of ischemic significance, in the left occipital lobe near tentorium. In order to prevent further embolization, emergency cardiac surgery (right atriotomy, removal of thrombus and closure of the PFO, pulmonary thrombectomy) was performed without complications. CONCLUSIONS: Although rare, the evidence of a thrombus stuck in a patent foramen ovale represents a clinical emergency. The optimal therapeutic approach is still debated. The surgical correction seems to be a safe and effective option for these patients.

Effect of Propofol, Sevoflurane and Desflurane on systemic redox balance.

We studied the effects of Propofol, Desflurane, and Sevoflurane on the systemic redox balance in patients undergoing laparohysterectomy. We measured blood concentration of glutathione (GSH), plasma antioxidant capacity (Trolox Equivalent Antioxidant Capacity-TEAC), and lipid peroxidation products (malondialdehyde (aMDA) and 4-hydroxynonenal (aHNE) protein adducts). Sixty patients were randomly placed into three groups of twenty people each. In Group P anesthesia was induced with Propofol 2 mg/kg and maintained with 12-10-8 mg/kg/min; in Groups S and D anesthesia was induced with 3 mg/kg Sodium Thiopental and maintained with 2 percent Sevoflurane and 6 percent Desflurane, respectively. Blood samples were collected prior to induction (T0 bas), 60min and 24h postoperatively (T1 60 and T2 24 h). In Group P, GSH increased on T1 60 and returned to baseline on T24h, while TEAC remained unmodified; in Groups S, GSH and TEAC decreased on T1 60 in Group D, on T1 60 there was a slight decrease of GSH and TEAC. The levels of aMDA slightly decreased throughout the study periods in Group P, increased in Group D, and remained stable in Group S. Propofol showed antioxidant properties, while Sevoflurane and Desflurane seemed to shift the redox balance towards oxidation, yet without inducing overt oxidative damage.

Prolonged remission of neuro-Behcet disease following autologous transplantation.

Two young male patients with severe progressive Behcet's disease with neurological involvement (N-BD) were treated by high-dose immunosuppressive chemotherapy (HIC) followed by autologous CD34+ selected peripheral blood stem cell transplantation (APBSCT). Neurological impairment and disability were quantified by means of Expanded Disability Status Scale (EDSS). Neuroimaging included spine and brain MRI and brain SPECT by radiolabeling technetium (Tc99m) Ethyl Cisteynate Dimer (ECD). Disease progression halted after treatment in both patients. At 48 months of follow-up they were therapy-free and one showed neurological status and disability improvement. Brain MRI findings were unchanged in both patients, but SPECT-ECD showed an increase of blood flow in the hypoperfused cerebral areas in the ameliorated patient. Immune ablation followed by APBSCT can modify the course of severe N-BD. Because of the high risk and the transplant-related mortality, these cases have to be carefully selected.