Acquired SERPINC1/antithrombin deficiency during oral contraceptive consumption: a case report.

BACKGROUND: SERPINC1 is a glycoprotein that regulates blood coagulation. SERPINC1 congenital or acquired deficiencies represent a significant risk factor for thromboembolic disease. SERPINC1 acquired defects are observed in very few cases and can occur in many clinical conditions such as treatment with L-asparaginase or oral contraceptive (particularly estrogen derivatives), but these conditions are not routinely investigated. CASE PRESENTATION: A 50-year-old Caucasian woman who took gestodene 75 µg/ethinylestradiol 20 µg as oral contraceptive, was sent to our thrombophilia clinic because, on thrombophilia testing, a reduction of SERPINC1 (74%) and a slight increase in circulating D-dimer and homocysteine were found. We investigated triggers of such SERPINC1 reduction, and identified gestodene 75 µg/ethinylestradiol 20 µg use as the most likely candidate. Two months after the discontinuation of the oral contraceptive, SERPINC1 value returned to normal (92%) and D-dimer and homocysteine were normalized. CONCLUSION: Each patient has a different sensitivity to contraceptive use. Genetic (or epigenetic) regulation of anticoagulant proteins might account for a different rate of consumption of anticoagulant proteins as oral contraceptives and probably determine the susceptibility to thrombotic events.

First-trimester prediction of gestational hypertension through the bioelectrical impedance analysis of the body composition.

OBJECTIVE: Obesity is a risk factor for the development of gestational hypertension, with important consequences for both the mother and fetus. This prospective observational study aims to propose an early prediction model of hypertensive disorders in pregnancy among obese women, through the bioelectrical impedance analysis (BIA) at the first trimester, thus allowing early recognition of obese women that are at risk to develop gestational hypertension, in order to target preventive interventions. PATIENTS AND METHODS: Singleton obese women (BMI ≥ 30 kg/m2) between the 9th and 12th week of pregnancy were included in the study. The exclusion criteria were chronic diseases, like type 2 diabetes mellitus, hypertension, and other medical pre-existing conditions. Eligible women were followed up at 20, 28, and 36 weeks of gestation by measuring blood pressure, weight, and body composition with the use of the BIA. The diagnosis of gestational hypertension was made after the 20th week of gestation. Pregnancy and perinatal outcomes were then recorded. RESULTS: Of the 479 women included in the study, 85 (17.7%) developed gestational hypertension; the remaining 394 (82.3%) resulted to be normotensive. A higher rate of nulliparous women was found in the hypertensive group (50.6% vs. 37.6%, p = 0.02), together with a higher rate of induction of labor (55.3% vs. 40.9%, p = 0.02) and of small for gestational age (SGA) newborns (12.9% vs. 6.9%, p = 0.03). Significant differences emerged in the body composition between the two groups already from the first trimester, indeed women developing gestational hypertension showed elevated values of Total body Mass, FM, FFM, TBW (p < 0.02), and of leg's FM, FFM (p < 0.006). At the multivariate logistics regression, the risk of developing gestational hypertension resulted higher in women with elevated total body water levels in the first trimester (OR 1.10 95% CI 1.04 -1.92). CONCLUSIONS: The BIA is a rapid, easy, non-invasive, and inexpensive tool to evaluate the body composition of obese pregnant women. It represents a promising predictor of hypertensive disorders in pregnancy, which allows an early identification of the patients at risk of developing gestational hypertension, thus opening a window of opportunity for strictly monitoring and target preventive intervention.

T cell-derived interferon-γ programs stem cell death in immune-mediated intestinal damage.

Despite the importance of intestinal stem cells (ISCs) for epithelial maintenance, there is limited understanding of how immune-mediated damage affects ISCs and their niche. We found that stem cell compartment injury is a shared feature of both alloreactive and autoreactive intestinal immunopathology, reducing ISCs and impairing their recovery in T cell-mediated injury models. Although imaging revealed few T cells near the stem cell compartment in healthy mice, donor T cells infiltrating the intestinal mucosa after allogeneic bone marrow transplantation (BMT) primarily localized to the crypt region lamina propria. Further modeling with ex vivo epithelial cultures indicated ISC depletion and impaired human as well as murine organoid survival upon coculture with activated T cells, and screening of effector pathways identified interferon-γ (IFNγ) as a principal mediator of ISC compartment damage. IFNγ induced JAK1- and STAT1-dependent toxicity, initiating a proapoptotic gene expression program and stem cell death. BMT with IFNγ-deficient donor T cells, with recipients lacking the IFNγ receptor (IFNγR) specifically in the intestinal epithelium, and with pharmacologic inhibition of JAK signaling all resulted in protection of the stem cell compartment. In addition, epithelial cultures with Paneth cell-deficient organoids, IFNγR-deficient Paneth cells, IFNγR-deficient ISCs, and purified stem cell colonies all indicated direct targeting of the ISCs that was not dependent on injury to the Paneth cell niche. Dysregulated T cell activation and IFNγ production are thus potent mediators of ISC injury, and blockade of JAK/STAT signaling within target tissue stem cells can prevent this T cell-mediated pathology.

Intravenous lipid infusion and total plasma fatty acids positively modulate plasma acylated ghrelin in vivo.

BACKGROUND & AIMS: Ghrelin is a gastric orexigenic hormone whose activating acylation plays a relevant role in the regulation of energy balance. Nutritional modulators of ghrelin acylation and plasma acylated ghrelin (AG) concentration remain however largely undefined. We aimed at investigating whether circulating free fatty acids (FFA) contribute to regulate plasma AG and its ratio (AG/TG) to total hormone (TG). METHODS: Plasma FFA, TG, AG and AG/TG were measured in a primary outpatient care setting in a community-based population cohort of 850 individuals (age 54 ± 10 years, M/F: 408/442) from the North-East Italy MoMa study. 150-min intravenous lipid infusions in rodents (10% lipids, 600 µl/h) were used to investigate the potential causal role of FFA in the regulation of plasma ghrelin profile. RESULTS: Plasma FFA were associated positively with AG and AG/TG while negatively with TG (P < 0.01). Associations between FFA, AG and AG/TG remained statistically significant (P < 0.02) in multiple regression analysis including HOMA insulin resistance and metabolic confounders, and both AG and AG/TG but not TG increased through plasma FFA quartiles (P < 0.01). Consistent with these findings, intravenous lipid infusion with plasma FFA elevation caused elevations of AG and AG/TG (P < 0.05) with no TG modifications. CONCLUSIONS: The current findings demonstrate a novel role for circulating FFA availability to up-regulate plasma AG, which could involve FFA-induced stimulation of ghrelin acylation.

Plasma total and unacylated ghrelin predict 5-year changes in insulin resistance.

BACKGROUND & AIMS: Ghrelin is a gastric hormone circulating in acylated (AG) and unacylated (UG) forms, and higher plasma total ghrelin (TG) and UG may be cross-sectionally associated with lower insulin resistance in metabolic syndrome patients. The potential value of ghrelin forms in predicting insulin resistance and its time-related changes in community-based population cohorts remains unknown. METHODS: We measured TG, AG and calculated UG (TG-AG) in 716 individuals from the North-East-Italy MoMa study (age: 55 ± 9 years, BMI: 29 ± 5 kg/m(2), M/F:349/367) to test the hypothesis that circulating TG and UG, but not AG are negatively associated with insulin resistance (HOMA). We further hypothesized that baseline TG and UG negatively predict 5-year HOMA changes in a 350-individual subgroup. RESULTS: Baseline TG and UG were associated negatively with HOMA after adjusting for gender and body mass index (BMI). Baseline gender- and BMI-adjusted TG and UG were also negatively associated with HOMA at 5-year follow-up (n = 350), and changes in TG and UG were negatively associated with changes in HOMA (P < 0.05) after adjustment for anthropometric and metabolic confounders. No statistically significant correlations were observed between AG and baseline or 5-year HOMA. CONCLUSIONS: In a North-East Italy community-based population cohort, plasma TG and UG but not AG are negatively associated with HOMA. TG and UG and their changes also independently predict 5-year HOMA changes. TG and UG are therefore novel potential modulators of insulin resistance and may contribute to predict its time-related changes in humans.

Psychological distress in patients with Charcot-Marie-Tooth disease.

AIM: Charcot-Marie-Tooth disease (CMT) is a genetic neuropathy that causes variable degrees of gait and handgrip impairment, and reduces quality of life. The large majority of CMT patients are moderately affected and lead almost a normal life despite facing numerous difficulties and physical and psychological suffering. This study is aimed at investigating the possible presence of psychological distress in this population. METHODS: Fifty-three patients (F=30, M=23; age: 16-64 years; disease duration: 1-53 years), with variable gait and handgrip impairments but still able to ambulate independently, referred to a specialized rehabilitation service, and 53 sex and age matched controls were administered with the Kellner's Symptom Questionnaire Italian validated version. RESULTS: The mean scores of patients, both as a whole and as divided in groups according to sex, age and lower limb impairment severity, did not differ significantly from those of controls (P>0.05). CONCLUSION: Patients with CMT are able to cope with the problems caused by their disease without developing more psychological distress than unaffected subjects, probably as the result of a comprehensive adaptation, favoured by the long disease duration, relative mildness of symptoms, good cognitive functioning and availability of rehabilitative resources.

Poor compliance with ankle-foot-orthoses in Charcot-Marie-Tooth disease.

AIM: The aim of this study is to evaluate the compliance with ankle-foot orthoses (AFOs) in patients previously prescribed and affected with Charcot-Marie-Tooth disease (CMT). METHODS: Twenty-five Italian patients (8 males 17 females; mean age: 41.6 years, range 16-54) with severe bilateral footdrop (leg-sole angle alpha >105 degrees ) alone or associated with other problems (rotation, plantarflexor failure, knee flexor failure) were examined by a physiatrist (with measurement of the leg-sole angle alpha' with their footwear) and interviewed by a psychologist. RESULTS: Only 5 patients (20%) used AFOs (3 prefabricated polypropylene AFOs, 2 custom-made short AFOs incorporated in high-top boots) with satisfactory functional results (alpha' <=94 degrees ; reported increased mobility and no more falls). The interview revealed that all patients had a bad relationship with their own body. The 3 subjects using prefabricated AFOs said that they hated them and one of them complained of pain. Patients not using AFOs justified their decision with statements such as: ''I am not yet ready to accept them'' (n=3) or ''I can still manage without them for a while'' (n=2) or both (n=15). Four patients had experienced pain during the trial, 2 had not found proper shoes to accommodate them and 12 were absolutely not interested in AFOs and, therefore, had not gone to an orthotist. CONCLUSION: Compliance with AFOs is poor. Patients with CMT discard AFOs because they highlight their disability, are not essential for their limited daily walking and are uncomfortable. We suggest that prescription of AFOs be accompanied with psychological support and that research of more comfortable and cosmetically acceptable solutions for the problem of footdrop be stimulated.

Persistence of range of motion in dorsiflexion, when the triceps surae muscles weaken, worsens stance and gait in Charcot-Marie-Tooth disease. A case report.

Charcot-Marie-Tooth disease is a genetically heterogeneous disorder, characterized by length dependent degeneration of motor and sensory nerve fibers. The variability in clinical severity is typical, and is considered the result of environmental factors interacting with the genotype. We report the case of 2 sisters who present the same muscle involvement, with complete atrophy below the knees, but a very different degree of disability: the milder affected sister can walk independently for 1 km, the more severe for 50 m only. The factor, responsible for the different functional impairment, is the persistence of ankle dorsiflexion. This is the result of prolonged stretching of the heel cords in the more severely affected sister, which destabilizes stance and ambulation. On the contrary, the milder affected sister presents a slight equinus deformity well compensated by wearing shoes with a bit of heel. The presented cases and biomechanics suggest that the persistence of range of motion in dorsiflexion, when the triceps surae muscles weaken beyond a certain degree, represents an important negative factor of clinical variability in Charcot-Marie-Tooth disease; this can be averted by correct rehabilitation management.

Handgrip impairment in Charcot-Marie-Tooth disease.

AIM: Charcot-Marie-Tooth disease (CMT) is a genetic neuropathy causing muscle weakening in the feet, legs and hands, with consequent impairment of ambulation and handgrip. For fast clinical evaluation and rehabilitation management of handgrip deficits, a functional classification in 4 stages or levels of clinical severity, based on the loss of handgrip types from the finest to the roughest, has been recently proposed. The aim of this study is to evaluate the prevalence of each level of handgrip impairment in a wide population of patients affected with demyelinating and axonal CMT. METHODS: Two-hundred and forty-eight non-operated hands were examined to evaluate if and how the pinch between the pulp of the thumb and the pulp of the second or third finger was made, starting from the palm-up position with the fingers abducted or, in case of impossibility to do so, if a lateral pinch or only a grasp was possible. Following to this observation, each hand was fitted in 1 of the 4 stages described in the above-mentioned classification and then the frequency of each stage was determined. RESULTS: As a whole, 75.4% hands were at stage 1; 9.7 were at stage 2; 10.9% at stage 3; 4% at stage 4. CONCLUSIONS: The results of this survey reveal that, in the majority of the CMT cases, handgrip is affected mildly so that only simple recommendations to prevent further muscle and joint damage are required; however, in more than 1 out 5 cases, the handrip impairment is quite severe and requires a detailed rehabilitative program with daily exercises, and, in a small number of cases, is so severe that independence in the daily living activities is lost or very reduced.

Quality of life in patients with Charcot-Marie-Tooth disease.

The authors evaluated quality of life in Charcot-Marie-Tooth disease by administering the Medical Outcome Study Short Form-36 (SF-36) questionnaire to 121 Italian patients. Patients scored lower on all of the SF-36 scales compared with Italian normative data. Scores were lower in nonworking vs working patients, women vs men, and older vs younger patients, but not between patients with demyelinating vs axonal forms or between patients who had undergone orthopedic foot surgery vs those who had not.