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Climate change and ambient air pollution are threats to human health, with dramatic short- and long-term effects on mortality and morbidity. Pollution generates fears among citizens who rarely receive adequate information for risk mitigation. A large burden of evidence is describing since decades the health effects of pollution, linking environmental exposure to pathophysiological mechanisms (mainly, low-grade chronic inflammation) that lead to an array of chronic non-communicable diseases. Epidemiologists are deeply involved to depict environment-related diseases, identify risk factors as well as to offer suggestions for prevention policies. However, their warnings are frequently disregarded by clinicians and policymakers. In clinical practice, diagnostic evidence is the basis for therapeutic interventions. Conversely, epidemiological evidence in the field of environmental health rarely generates appropriate preventive and clinical actions. Despite the great interest and concerns of citizens and epidemiologists, the perception of pollution as a major hazard to health is often scarce among clinicians, as witnessed by the poor presence of environmental health in the majority of clinical guidelines, meetings of scientific societies, and medical curricula. As a consequence, inaction is not uncommon among clinicians, who often fail to routinely engage in counseling their patients on how to reduce their health risks from living in an unsafe environment nor to act as advocates in order to enact changes in the community. This gap should be urgently bridged by creating opportunities for health professionals to be adequately informed and trained to play an active role in tackling environmental risks., (© 2024. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

The fight against obesity is largely based on recommendations about lifestyle and therapies to initiate weight loss and, hopefully, to achieve and maintain an ideal weight. The failure of this approach is witnessed by the steady increasing rates of obesity worldwide. Lifestyle modifications yield mild weight loss with poor results in the long-term. The pharmaceutical industry is engaged to produce the best anti-obesity drugs, and this market is projected to grow massively. Guidelines on pharmacological and surgical approach to obesity are continuously developed, taking into account that benefits are counterbalanced by high costs, are limited to the period of drug intake, and potential adverse effects are possible, such as pancreatitis, gastroparesis, and bowel obstruction. Meantime, people living with obesity might simply think that taking the "magic pill" or undergoing bariatric surgery can change their life. In the long term, this tendency might lead to scarce cost-effectiveness, increasing adverse effects and inequities in the most vulnerable age classes. Furthermore, the main actors responsible for generating an obesogenic world will continue undisturbed to produce negative effects. Obesity is not only generated from voluntary individual behaviors, and no guideline can truly counteract the detrimental effects of environmental factors driving the progressive rise of obesity globally. Unsustainable food production, packaging and marketing, environmental pollution, widely diffused endocrine disrupting chemicals, and climate change are largely neglected by health professionals and generate food insecurity and malnutrition. The complexity of obesity cannot be managed only pointing to individual responsibilities of people living with obesity. There is a missing link here, and this war cannot be won in the absence of effective primary prevention measures involving changes in food production and marketing, and decreased release of toxic chemicals into the environment., (© 2024. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Chronic heart failure is the most common cause of hospitalization in Europe and rates are steadily increasing due to aging of the population. Hospitalization identifies a fundamental change in the natural history of heart failure (HF) increasing the risk of re-hospitalization and mortality. Heart failure management programs improve the quality of care for HF patients and reduce hospitalization burden. The goals of the heart failure management programs include optimization of drug therapy, patient education, early recognition of signs of decompensation, and management of comorbidities. Randomized clinical trials evidenced that system of care for heart failure patients improved adherence to treatment and reduced unplanned re-admissions to hospital. Multidisciplinary programs and home-visiting have shown improved efficacy with reductions in HF and all-cause hospitalizations and mortality. Community HF clinics should take care of the management of stable patients in strict contact with primary care, while hospital out-patients clinics should care of patients with severe disease or persistent clinical instability, candidates to advanced treatment options. In any case a holistic, patient-centered approach is suggested, to optimize care considering the needs of the individual patient. Telemonitoring is a new opportunity for HF patients, because it allows the continuity of care at home. All heart failure patients should require follow-up in a specific management program, but most of date come from clinical trials that included high-risk patients. While clinical trials have a specified duration (from months to some years), lifelong follow-up is recommended with differentiated approaches according to the patient's need., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Bile acids (BA) are amphipathic molecules originating from cholesterol in the liver and from microbiota-driven biotransformation in the colon. In the gut, BA play a key role in fat digestion and absorption and act as potent signaling molecules on the nuclear farnesoid X receptor (FXR) and membrane-associated G protein-coupled BA receptor-1 (GPBAR-1). BA are, therefore, involved in the maintenance of gut barrier integrity, gene expression, metabolic homeostasis, and microbiota profile and function. Disturbed BA homeostasis can activate pro-inflammatory pathways in the gut, while inflammatory bowel diseases (IBD) can induce gut dysbiosis and qualitative and/or quantitative changes of the BA pool. These factors contribute to impaired repair capacity of the mucosal barrier, due to chronic inflammation. A better understanding of BA-dependent mechanisms paves the way to innovative therapeutic tools by administering hydrophilic BA and FXR agonists and manipulating gut microbiota with probiotics and prebiotics. We discuss the translational value of pathophysiological and therapeutic evidence linking BA homeostasis to gut inflammation in IBD., (© 2023. The Author(s).)

About 20% of adults worldwide have gallstones which are solid conglomerates in the biliary tree made of cholesterol monohydrate crystals, mucin, calcium bilirubinate, and protein aggregates. About 20% of gallstone patients will definitively develop gallstone disease, a condition which consists of gallstone-related symptoms and/or complications requiring medical therapy, endoscopic procedures, and/or cholecystectomy. Gallstones represent one of the most prevalent digestive disorders in Western countries and patients with gallstone disease are one of the largest categories admitted to European hospitals. About 80% of gallstones in Western countries are made of cholesterol due to disturbed cholesterol homeostasis which involves the liver, the gallbladder and the intestine on a genetic background. The incidence of cholesterol gallstones is dramatically increasing in parallel with the global epidemic of insulin resistance, type 2 diabetes, expansion of visceral adiposity, obesity, and metabolic syndrome. In this context, gallstones can be largely considered a metabolic dysfunction-associated gallstone disease, a condition prone to specific and systemic preventive measures. In this review we discuss the key pathogenic and clinical aspects of gallstones, as the main clinical consequences of metabolic dysfunction-associated disease., (© 2023. The Author(s).)

Obesity has reached epidemic proportion worldwide and in all ages. Available evidence points to a multifactorial pathogenesis involving gene predisposition and environmental factors. Gut microbiota plays a critical role as a major interface between external factors, i.e., diet, lifestyle, toxic chemicals, and internal mechanisms regulating energy and metabolic homeostasis, fat production and storage. A shift in microbiota composition is linked with overweight and obesity, with pathogenic mechanisms involving bacterial products and metabolites (mainly endocannabinoid-related mediators, short-chain fatty acids, bile acids, catabolites of tryptophan, lipopolysaccharides) and subsequent alterations in gut barrier, altered metabolic homeostasis, insulin resistance and chronic, low-grade inflammation. Although animal studies point to the links between an "obesogenic" microbiota and the development of different obesity phenotypes, the translational value of these results in humans is still limited by the heterogeneity among studies, the high variation of gut microbiota over time and the lack of robust longitudinal studies adequately considering inter-individual confounders. Nevertheless, available evidence underscores the existence of several genera predisposing to obesity or, conversely, to lean and metabolically health phenotype (e.g., Akkermansia muciniphila, species from genera Faecalibacterium, Alistipes, Roseburia). Further longitudinal studies using metagenomics, transcriptomics, proteomics, and metabolomics with exact characterization of confounders are needed in this field. Results must confirm that distinct genera and specific microbial-derived metabolites represent effective and precision interventions against overweight and obesity in the long-term., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this thematic issue on phenotyping the obesities, prominent international experts offer an insightful and comprehensive collection of articles covering the current knowledge in the field. In order to actually capture all the polyhedral determinants of the diverse types of obesity, the granularity of the phenotypic information acquired must be expanded in the context of a personalized approach. Whilst the use of precision medicine has been successfully implemented in areas like cancer and other diseases, health care providers are more reluctant to embrace detailed phenotyping to guide diagnosis, treatment and prevention in obesity. Given its multiple complex layers, phenotyping necessarily needs to go beyond the multi-omics approach and incorporate all the diverse spheres that conform the reality of people living with obesity. Potential barriers, difficulties, roadblocks and opportunities together with their interaction in a syndemic context are analyzed. Plausible lacunae are also highlighted in addition to pointing to the need of redefining new conceptual frameworks. Therefore, this extraordinary collection of state-ofthe-art reviews provides useful information to both experienced clinicians and trainees as well as academics to steer clinical practice and research in the management of people living with obesity irrespective of practice setting or career stage., (© 2023. The Author(s).)

Following the COVID-19 discovery in December 2019, different vaccines were authorized in 2021 in Italy and Lebanon, but side effects and the impact of sex and age remained partly explored. We designed a web-based "Google Form" questionnaire to record self-reported systemic and local side effects up to 7 days after 1st and 2nd dose of the vaccine in two distinct Italian and Lebanese cohorts. Twenty-one questions in Italian and Arabic languages explored the prevalence and severity of 13 symptoms. Results were compared with respect to living country, timing, sex, and age classes. A total of 1,975 Italian subjects (age 42.9 ± SD16.8 years; 64.5% females) and 822 Lebanese subjects (age 32.5 ± SD15.9 years; 48.8% females) joined the study. The most common symptoms in both groups were injection site pain, weakness, and headache after the 1st and 2nd doses. The rate of post-vaccinal symptoms and the severity score were significantly higher in females than in males and progressively decreased with increasing age following both doses. We find that among two populations from the Mediterranean basin, the anti-COVID-19 vaccine generates mild age and sex-dependent adverse effects, with ethnic differences and prevalent symptoms rate and severity in females., (© 2023. The Author(s).)

The term non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common type of chronic liver disease. NAFLD points to excessive hepatic fat storage and no evidence of secondary hepatic fat accumulation in patients with "no or little alcohol consumption". Both the etiology and pathogenesis of NAFLD are largely unknown, and a definitive therapy is lacking. Since NAFLD is very often and closely associated with metabolic dysfunctions, a consensus process is ongoing to shift the acronym NAFLD to MAFLD, i.e., metabolic-associated fatty liver disease. The change in terminology is likely to improve the classification of affected individuals, the disease awareness, the comprehension of the terminology and pathophysiological aspects involved, and the choice of more personalized therapeutic approaches while avoiding the intrinsic stigmatization due to the term "non-alcoholic". Even more recently, other sub-classifications have been proposed to concentrate the heterogeneous causes of fatty liver disease under one umbrella. While awaiting additional validation studies in this field, we discuss the main reasons underlying this important shift of paradigm., (© 2023. The Author(s).)

The first COVID-19 lockdown resulted in enforced quarantine of heavily affected areas with social isolation and related measures by several governments to slow the spread of the disease. The general population experienced several mental and lifestyle changes. Herein, we aimed to evaluate the metabolic and psychological effects induced by lifestyle changes during COVID-19 self-isolation among an Apulian overweight/obese cohort with metabolic disturbances. The study assessed anthropometric data (weight, abdominal circumferences), dietary habits (adherence to the Mediterranean diet, junk food score), lifestyle habits (i.e., smoking, and physical activity), levels of stress and anxiety, and depression. Subjects underwent bioumoral exams before and after self-isolation to monitor glycemic and lipid profiles. A total of 245 subjects (M:F = 118:127) have been included in the study. After lockdown, the number of obese subjects significantly increased in both sexes, and was higher in females than in males (P < 0.0001). Glycemic and lipid profiles worsened, with higher levels of insulinemia, lower levels of HDL cholesterol, and higher levels of triglycerides in females than in males. Adherence to the Mediterranean diet and consumption of junk foods were altered in both groups, especially in females. Psychological aspects were significantly higher in females than in males. Finally, work activities and familial status strongly affected the metabolic and psychological profile. In conclusion, COVID-19 self-isolation induced changes in lifestyle and dietary habits with psychological distress and detrimental effects on metabolic patterns, which were more pronounced in female gender., (© 2023. The Author(s).)

Internists are experts in complexity, and the COVID-19 pandemic is disclosing complex and unexpected interactions between communicable and non-communicable diseases, environmental factors, and socio-economic disparities. The medicine of complexity cannot be limited to facing comorbidities and to the clinical management of multifaceted diseases. Evidence indicates how climate change, pollution, demographic unbalance, and inequalities can affect the spreading and outcomes of COVID-19 in vulnerable communities. These elements cannot be neglected, and a wide view of public health aspects by a "one-health" approach is strongly and urgently recommended. According to World Health Organization, 35% of infectious diseases involving the lower respiratory tract depend on environmental factors, and infections from SARS-Cov-2 is not an exception. Furthermore, environmental pollution generates a large burden of non-communicable diseases and disabilities, increasing the individual vulnerability to COVID-19 and the chance for the resilience of large communities worldwide. In this field, the awareness of internists must increase, as privileged healthcare providers. They need to gain a comprehensive knowledge of elements characterizing COVID-19 as part of a syndemic. This is the case when pandemic events hit vulnerable populations suffering from the increasing burden of chronic diseases, disabilities, and social and economic inequalities. Mastering the interplay of such events requires a change in overall strategy, to adequately manage not only the SARS-CoV-2 infection but also the growing burden of non-communicable diseases by a "one health" approach. In this context, experts in internal medicine have the knowledge and skills to drive this change., (© 2022. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Previous ecological studies suggest the existence of possible interplays between the exposure to air pollutants and SARS-CoV-2 infection. Confirmations at individual level, however, are lacking. To explore the relationships between previous exposure to particulate matter < 10 μm (PM 10 ) and nitrogen dioxide (NO 2 ), the clinical outcome following hospital admittance, and lymphocyte subsets in COVID-19 patients with pneumonia. In 147 geocoded patients, we assessed the individual exposure to PM 10 and NO 2 in the 2 weeks before hospital admittance. We divided subjects according to the clinical outcome (i.e., discharge at home vs in-hospital death), and explored the lymphocyte-related immune function as an index possibly affecting individual vulnerability to the infection. As compared with discharged subjects, patients who underwent in-hospital death presented neutrophilia, lymphopenia, lower number of T CD45, CD3, CD4, CD16/56 + CD3 + , and B CD19 + cells, and higher previous exposure to NO 2 , but not PM 10 . Age and previous NO 2 exposure were independent predictors for mortality. NO 2 concentrations were also negatively related with the number of CD45, CD3, and CD4 cells. Previous NO 2 exposure is a co-factor independently affecting the mortality risk in infected individuals, through negative immune effects. Lymphopenia and altered lymphocyte subsets might precede viral infection due to nonmodifiable (i.e., age) and external (i.e., air pollution) factors. Thus, decreasing the burden of air pollutants should be a valuable primary prevention measure to reduce individual susceptibility to SARS-CoV-2 infection and mortality., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

An 86-year-old Caucasian man had prior episodes of fever (up to 38 °C), mild abdominal pain, tachycardia, and malaise in the last 3 months, lasting 2-3 days. He never suffered from abdominal or chest pain, rash, or arthralgia. Major causes of fever were excluded (pulmonary, urinary, abdomen, skin infections, neoplasms, and major rheumatologic disorders). The patient was native of Altamura with a family history of familial Mediterranean fever (FMF). The genetic testing confirmed the presence of MEFV gene variants c.442G>C (E148Q) on exon 2 and c.2282G>A (R761H) on exon 10, all in heterozygosity. Mildly elevated serum transaminases suggested an ongoing form of FMF hepatitis on nonalcoholic liver steatosis. The patient started colchicine 1 mg/day that induced symptom control and normalization of inflammatory markers, hyperbilirubinemia, and markers of cholestasis. Symptoms of FMF can appear at any age in life and our patient represents a very late-onset clinical case. The Apulian region has a consistent clustering of MEFV variants and FMF families with affected individuals in multiple consecutive generations. Families show unique clinical features and rare signs of secondary amyloidosis without kidney damage. Genetic and environmental bases of this phenotypic variant are under scrutiny. Colchicine lifetime remains the mainstay of treatment in FMF patients. KEY POINTS: • Familial Mediterranean fever (FMF) is the most frequent hereditary monogenic recurrent fever syndrome, and symptoms can appear at any age in life. • Late-onset FMF approaches 30% in late adulthood, but in general, onset of FMF after the age of 40 (late onset FMF) is rare, usually associated with M694V heterozygosity. • In a local cluster of FMF families (Altamura, Puglia, Southern Italy), we report a very late-onset FMF (variants E148Q, R761H) in an 86-year-old patient with a positive family history of FMF in two generations of descendants. • While lifetime colchicine remains the mainstay of treatment in FMF patients, prospective studies need to identify the characteristics of several phenotypic variants accounting for (very)-late onset FMF.

Chronic heart failure (CHF) is one of the main disabilities in elderly patients requiring frequent hospitalizations with high health care costs. We studied the outcome of CHF outpatient management in reducing hospitalization after discharge from a division of Internal Medicine at a large 3rd referral regional Hospital. 147 CHF inpatients (M:F: 63:84; mean age 76 ± 9.6 years) admitted for acute exacerbation of CHF were followed up as outpatients at 1, 6, 12 and 24 months after discharge. At baseline, patients underwent: laboratory tests, ECG, echocardiogram and a dedicated-intensive health care educational program involving also their families. The rate of hospitalization in the same group of patients was compared with data from the previous 24 months, a period when patients had been seen elsewhere without disease management programs. Patients had high prevalence of comorbidities and the majority was in NYHA class III or IV. Hypertension and valvular heart disease were the most common causes for CHF. Systolic function was preserved (LVEF ≥ 50%) in 61.9% of cases. Functional NYHA class improved significantly after 6 months and remained stable at 24 months. There was a significant increase in the use of the renin-angiotensin system blockers, beta-blockers and diuretics compared to admission to the ward. At 24 months, hospital readmissions were decreased by 42% as compared to the previous 24 months. Risk factors for re-hospitalizations were anemia, NYHA class III or IV and previous hospitalizations. Establishing an intensive outpatient management program for CHF patients leads to long-term beneficial effects with improved clinical parameters and decreased hospitalization in the setting of Internal Medicine.

Purpose: Aims of this study were to evaluate the agreement between the short and long versions of the International Physical Activity Questionnaire (IPAQ: Italian versions), their reproducibility (agreement and reliability) and construct validity (relative to pedometry) in a clinical population., Methods: Ninety patients affected by obesity (N = 39), type 2 diabetes mellitus (N = 26) or both (N = 25) were recruited. They were asked to maintain their usual physical activity habits during two consecutive weeks and to fill the questionnaires twice (at the end of each week). They were also asked to wear a pedometer for 7 consecutive days after the first administration of the questionnaires., Results: We found acceptable agreement between the IPAQ short and long versions (ICC 2,1 values were 0.81 and 0.77 for the 1st and 2nd administration), uncertain reproducibility (acceptable reliability but poor agreement) and inadequate validity relative to pedometry (the correlation coefficients between all IPAQ scores and daily steps were <0.50) for both IPAQ short and IPAQ long., Conclusions: The IPAQ use may be justified in daily clinical practice and in clinical research (e.g., in cross-sectional studies) for a simple and rapid evaluation of the physical activity level for discriminative purposes. However, the use of these questionnaires does not appear suitable for prospective interventional studies in which the level of physical activity of the recruited patients has to be assessed over time.

The purpose of this review is to evaluate whether some risk factors in childhood work as significant predictors of the development of obesity and the metabolic syndrome in adulthood. These factors include exposures to risk factors in the prenatal period, infancy and early childhood, as well as other socio-demographic variables. We searched articles of interest in PubMed using the following terms: 'predictors AND obesity OR Metabolic syndrome AND (children OR adolescents) AND (dyslipidemia OR type 2 diabetes OR atherosclerosis OR hypertension OR hypercholesterolemia OR cardiovascular disease)' AND genetic OR epigenetic. Maternal age, smoking and weight gain during pregnancy, parental body mass index, birth weight, childhood growth patterns (early rapid growth and early adiposity rebound), childhood obesity and the parents' employment have a role in early life. Furthermore, urbanization, unhealthy diets, increasingly sedentary lifestyles and genetic/epigenetic variants play a role in the persistence of obesity in adulthood. Health promotion programs/agencies should consider these factors as reasonable targets to reduce the risk of adult obesity. Moreover, it should be a clinical priority to correctly identify obese children who are already affected by metabolic comorbidities.

Mucins are high molecular weight epithelial proteins, strongly glycosylated, and are the main component of the mucus. Since mucus secretion can be altered in diseases, colon mucins can be regarded as a biomarker of chronic inflammatory bowel diseases or preneoplastic changes. Conventional histochemistry and lectin histochemistry combined with chemical treatment and enzymatic digestion were carried out to analyze the colon mucins in mice fed a high-fat diet for 25 weeks, a period sufficient to induce simple liver steatosis, to check whether the carbohydrate features of mucus can be altered by an inadequate diet. An increase in the sialo/sulfomucins ratio with respect to control mice, assessed by computerized image analysis, was observed in the colon, although differences in sialic acid acetylation between control and mice fed a high-fat diet were not found. High-fat diet was also associated with altered lectin-binding pattern of the mucus, with a probable shortening of oligosaccharide chains of glycoproteins. This pattern was leading to over-expression of Galβ1,3GalNAc terminal dimers (TF antigen) and GalNAc terminal residues (Tn antigen). This altered composition of mucins can be related to a defect in the process of glycosylation, or to incomplete maturation of goblet cells, and may be an early indication of preneoplastic and neoplastic changes. In conclusion, our findings confirm that a fatty-rich diet (Western-style diet) induces alteration of mucins and may be associated with colon diseases. Our investigation corroborates the usefulness of lectins histochemistry in the early diagnosis of prepathological states of the colon.

Background: Successful bowel preparation is essential to an adequate performance of colonoscopy. Polyethylene glycol (PEG) with electrolyte solutions induces diarrhea with depletion of substrates fermentable by hydrogen (H2)-producing colonic microbiota. Inulin has recently been suggested as a prebiotic substrate for the H2 breath test because it is resistant to intestinal hydrolysis and is fermented mostly by the colonic bacteria. This study aimed to assess time-dependent changes in H2 breath levels in order to predict the colonic preparation of patients scheduled for colonoscopy with or without oral supplementation of inulin., Methods: In this prospective nonrandomized trial, 127 subjects drank 4 l of PEG 280-mg solution as bowel preparation for colonoscopy. A subgroup of 31 patients also ingested inulin (10 g in 200 ml of water) at breakfast as an additional substrate to increase colonic H2 production. Measurements of H2 breath levels were performed immediately before and after colonic preparation. As the main outcome measure, the quality of the colonic preparation was scored as excellent to fair (i.e., clean bowel allowing successful pan-colonoscopy, including the terminal ileum) or poor (incomplete colonoscopy due to fecal debris)., Results: The H2 breath levels decreased from 11.0 ± 1.8 ppm before PEG to 1.8 ± 0.3 ppm after PEG (n = 18; P < 0.001). The H2 concentrations after PEG ingestion were significantly lower (P < 0.001) in the patients with excellent-to-fair preparation than in the 19 patients with poor preparation. Ingestion of inulin induced an overall increase in H2 breath levels and improved discrimination between the patients with excellent-to-fair colonic preparation and those with poor preparation, leading to the sensitivity and specificity of such a test reaching 100 %., Conclusions: The H2 breath test with inulin ingestion can be a simple, noninvasive, reliable method for predicting successful colonic preparation that leads to cost savings and less patient discomfort/stress or need to repeat colonoscopy.

Purpose: To compare the outcome in patients with cervical goiters and cervicomediastinal goiters (CMGs) undergoing total thyroidectomy using the cervical or extracervical approach., Methods: This was a retrospective study conducted at six academic departments of general surgery and one endocrine-surgical unit in Italy. The study population consisted of 19,662 patients undergoing total thyroidectomy between 1999 and 2008, of whom 18,607 had cervical goiter (group A) and 1055 had CMG treated using a cervical approach (group B, n = 986) or manubriotomy (group C, n = 69). The main parameters of interest were symptoms, gender, age, operative time, duration of drain, length of hospital stay, malignancy and outcome., Results: A split-sternal approach was required in 6.5% of cases of CMG. Malignancy was significantly more frequent in group B (22.4%) and group C (36.2%) versus group A (10.4%; both P < .001), and in group C versus group B (P = .009). Overall morbidity was significantly higher in groups B + C (35%), B (34.4%) and C (53.5%) versus group A (23.7%; P < .001). Statistically significant increases for group B + C versus group A were observed for transient hypocalcemia, permanent hypocalcemia, transient recurrent laryngeal nerve (RLN) palsies, permanent RLN palsies, phrenic nerve palsy, seroma/hematoma, and complications classified as other. With the exception of transient bilateral RLN palsy, all of these significant differences between group B + C versus group A were also observed for group B versus group A., Conclusions: Symptoms, malignancy, overall morbidity, hypoparathyroidism, RLN palsy and hematoma are increased in cases of substernal goiter.

The response of fatty liver to stress conditions (t-butyl hydroperoxide [t-BH] or 36 h of fasting) was investigated by assessing intracellular glutathione (GSH) compartmentation and redox status, GSH peroxidase (GSH-Px) and reductase (GSSG-Rx) activities, lipid peroxidation (TBARs) and serum ALT levels in rats on a choline-deficient diet. Baseline cytosolic GSH was similar between fatty and normal livers, while the mitochondrial GSH content was significantly lower in fatty livers. With the except of cytosolic GSH-Px activity, steatosis was associated with significantly higher GSH-related enzymes activities. Liver TBARs and serum ALT levels were also higher. Administration of t-BH significantly decreased the concentration of cytosolic GSH, increased GSSG levels in all the compartments, and increased TBARs levels in cytosol and mitochondria and serum ALT; all these alterations were more marked in rats with fatty liver. Fasting decreased the concentration of GSH in all the compartments both in normal and fatty livers, increased GSSG, TBARs and ALT levels, and decreased by 50% the activities of GSH-related enzymes. Administration of diethylmaleimide (DEM) resulted in cytosolic and microsomal GSH pool depletion. Administration of t-BH to DEM-treated rats further affected cytosolic GSH and enhanced ALT levels, whereas the application of fasting to GSH depleted rats mainly altered the mitochondrial GSH system, especially in fatty livers. This study shows that fatty livers have a weak compensation of hepatic GSH regulation, which fails under stress conditions, thus increasing the fatty liver's susceptibility to oxidative damage. Differences emerge among subcellular compartments which point to differential adaptation of these organelles to fatty degeneration.