Gitelman syndrome associated with chondrocalcinosis and severe neuropathy: a novel heterozygous mutation in SLC12A3 gene.

Gitelman syndrome (GS) is an inherited salt-wasting tubulopathy characterized by hypocalciuria, hypokalemia, hypomagnesemia and metabolic alkalosis, due to inactivating mutations in the SLC12A3 gene. Symptoms may be systemic, neurological, cardiovascular, ophthalmological or musculoskeletal. We describe a 70 year-old patient affected by recurrent arthralgias, hypoesthesia and hyposthenia in all 4 limbs and severe hypokalemia, complicated by atrial flutter. Moreover, our patient reported eating large amounts of licorice, and was treated with medium-high dosages of furosemide, thus making diagnosis very challenging. Genetic analysis demonstrated a novel heterozygous mutation in the SLC12A3 gene; therefore, we diagnosed GS and started potassium and magnesium replacement. GS combined with chondrocalcinosis and neurological involvement is quite common, but this is the first case of an EMG-proven severe neuropathy associated with GS. Herein, we underline the close correlation between hypomagnesemia, chondrocalcinosis and neurological involvement. Moreover, we report a new heterozygous mutation in exon 23 (2738G>A), supporting evidence of a large genetic heterogeneity in this late-onset congenital tubulopathy.

Effects of transcranial magnetic stimulation on cocaine addiction: A systematic review of randomized controlled trials.

OBJECTIVE: While pharmacological strategies appear to be ineffective in treating long-term addiction, repetitive transcranial magnetic stimulation (rTMS) is emerging as a promising new tool for the attenuation of craving among multiple substance dependent populations. METHOD: A systematic review of randomized controlled trials (RCTs) was conducted on the efficacy and tolerability of rTMS in treating cocaine use disorder (CUD). Relevant papers published in English through November 30th 2022 were identified, searching the electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Library. RESULTS: Eight studies matched inclusion criteria. The best findings were reported by the RCTs conducted at high-frequency (≥5 Hz) multiple sessions of rTMS delivered over the left dorsolateral prefrontal cortex (DLPFC): a significant decrease in self-reported cue-induced cocaine craving and lower cocaine craving scores and a considerable amelioration in the tendency to act rashly under extreme negative emotions (impulsivity) were found in the active group compared to controls. CONCLUSION: Although still scant and heterogeneous, the strongest evidence so far on the use of rTMS on individuals with CUD support the high frequency stimulation over the left DLPFC as a well tolerated treatment of cocaine craving and impulsivity.

[Disease activity assessment in large vessel vasculitis]. / Valutazione dell'attività di malattia nelle vasculiti dei grandi vasi.

Disease activity assessment in large vessel vasculitis (LVV) is often challenging for physicians. In this study, we compared the assessment of disease activity based on inflammatory markers, clinical indices (Indian Takayasu Activity Score [ITAS] and the Kerr/National Institute of Health indices [Kerr/NIH]), and 18F-Fluorodesossiglucose (FGD) vascular uptake at positron emission tomography (Pet). We found that Pet results did not statistically correlate with the clinical indices ITAS and Kerr/NIH, because FDG uptake was increased (grade>2 on a 0-3 scale in at least one evaluated vascular segment) in many patients with inactive disease according to clinical and laboratory parameters (i.e., negative ITAS and Kerr/NIH indices as well as normal erythrocyte sedimentation rate (ESR) and C-reactive protein (PCR)). Similarly, interleukin- 6 and its soluble receptor did not statistically correlate with disease activity. In contrast, clinical indices showed a significant correlation between each other and with inflammatory markers (VES and PCR). These data suggest that while clinical indices and inflammatory markers may be useful to assess disease activity, Pet may be more sensitive.

Two-dimensional sensitivity analysis of MIPAS observations.

In this paper we propose a new approach to operate two-dimensional sensitivity studies on the observations of MIPAS, an experiment on board the ENVISAT satellite. The proposed analysis system is intended to evaluate the amount and the spatial distribution of the information that is carried by MIPAS observations with respect to the target atmospheric parameters. The new approach enables the definition and assessment of the target-dependent atmospheric sampling of the measurements. The amount of information is evaluated by merging MIPAS measurements, relative to different limb-scans, in a two-dimensional analysis that models the sensitivity of the spectral signals combined with the geometrical redundancy introduced by different observation geometries. The spatial distribution of the information that is obtained with our analysis highlights the advantage of using a two-dimensional retrieval system. Furthermore, within the two-dimensional context, this analysis provides crucial indications for the definition of the optimal retrieval grid and, therefore, for the best exploitation of existing measurements. The proposed analysis is also suited for the design of optimized observation strategies. The sensitivity analysis, applied in this paper to MIPAS observations, can be extended to other orbiting limb sounders that, like MIPAS, continuously measure the atmospheric emission along the orbit track.

Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer.

Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER hormone binding domain, where they are likely to be single allele mutations. Understanding how these mutations impact on ER function is a prerequisite for identifying methods to treat breast cancer patients featuring such mutations. Towards this end, we used CRISPR-Cas9 genome editing to make a single allele knock-in of the most commonly mutated amino acid residue, tyrosine 537, in the estrogen-responsive MCF7 breast cancer cell line. Genomic analyses using RNA-seq and ER ChIP-seq demonstrated that the Y537S mutation promotes constitutive ER activity globally, resulting in estrogen-independent growth. MCF7-Y537S cells were resistant to the anti-estrogen tamoxifen and fulvestrant. Further, we show that the basal transcription factor TFIIH is constitutively recruited by ER-Y537S, resulting in ligand-independent phosphorylation of Serine 118 (Ser118) by the TFIIH kinase, cyclin-dependent kinase (CDK)7. The CDK7 inhibitor, THZ1 prevented Ser118 phosphorylation and inhibited growth of MCF7-Y537S cells. These studies confirm the functional importance of ER mutations in endocrine resistance, demonstrate the utility of knock-in mutational models for investigating alternative therapeutic approaches and highlight CDK7 inhibition as a potential therapy for endocrine-resistant breast cancer mediated by ER mutations.

Morphological changes in rat pancreatic acinar cells induced by long-term treatment with cyclosporine and their reversal after withdrawal.

Cyclosporine (CsA), administered to rats at daily doses of 10 and 50 mg/kg body weight, for 21 days, influenced negatively the structures involved in the synthesis, storage and secretion of digestive enzymes in pancreatic acinar cells. A dose-related, significant reduction in basophilic cell regions, secretion granule content, and overall size of acinar cells was appreciable by light microscopy and morphometry. By electron microscopy, the acinar cells of the rats given 10 mg/kg/day CsA were similar to the controls, whereas with the higher dose most cells showed reduction in the size of nucleoli, increase in the number of lysosomes, and evidence of autophagy. In only a few cells was autophagy particularly severe and involved almost the entire cytoplasm. Nine weeks after withdrawal from CsA treatment, the structural recovery of acinal cells was complete, and features indicating enhanced protein synthesis and mitochondrial multiplication were observed by electron microscopy. In conclusion, prolonged administration of CsA to rats induces changes in the acinar cells indicating a depression of their activity, without substantial impairment in the viability of the most of them, even at high doses. This accounts for complete restoration of the acinar tissue upon withdrawal.

Estrogen replacement therapy in the management of osteopenia related to eating disorders.

The effect of hormone replacement therapy on the bone mineral content of hypoestrogenic subjects depends on the pathogenesis of the disease as well as on the dosage and route of administration. This is particularly true in hypoestrogenism related to eating disorders. We present a longitudinal study of 26 young women with diet-induced amenorrhea compared with a group of subjects with POF. The study protocol included the quantification of weight loss, the endocrine profile (follicle-stimulating hormone, luteinizing hormone, prolactin, E2, FT3, FT4, thyroid-stimulating hormone, and cortisol), the evaluation of markers of bone turnover (GLA, OSTK-PR, ALP, OHP, and DPYR), and spinal bone density by DEXA at observation and after weight recovery. No hormone replacement therapy was administered. Mean BMD and Z scores before and after recovery do not differ significantly; OHP and DPYR appear significantly higher during basal evaluation, whereas GLA and ALP do not. Data on the impact of oral contraceptive use on bone mineral density are controversial. We particularly discuss the question of long-term treatment with 20 micrograms ethinyl estradiol pills on peak bone mass acquisition during adolescence.

[Obesity and diabetes mellitus]. / L'obesità ed il diabete.

Prevention of obesity is the first step in management of diabetes mellitus type 2, but prevention programmes have had poor long-term efficacy. The cornerstones of treatment in obese type 2 diabetic patients are diet, physical activity and behavioural modifications. A small weight loss results in improvement of type 2 diabetic patients. The obese type 2 diabetic patient shows extra impediments to weight loss, such as the adverse effects of diabetic medications. New drugs, as orlistat and sibutramine, can offer some additional help, by providing the benefit associated with weight loss. Bariatric surgery can produce major long-term weight loss in severely obese patients.

Hardiness, self-perceived health, and activity among independently functioning older adults.

As the older population continues its rapid rise, it becomes increasingly important to identify variables that contribute to the quality of life--that which the gerontological literature refers to as "successful aging." Since most studies have supported activity as the most satisfying pattern of aging, the notion that hardiness of personality and self-perception of health are related to activity levels was tested in a group of independently functioning older adults (n = 115). The obtained significant correlations between hardiness and self-perceived health were -.293 (p less than .001, hardiness is negatively scored), and .210 (p less than .01), respectively. Together these variables explained 10% of the variance in activity. The sub-variable challenge, within the hardiness construct, did not correlate with activity, thereby diminishing the composite score of hardiness and activity. These data support existing studies of perceptual and activity theories, the theoretical links between the constructs, and have identified hardiness as an antecedent variable of successful aging.

Medical diagnostic reasoning: epistemological modeling as a strategy for design of computer-based consultation programs.

The complexity of cognitive emulation of human diagnostic reasoning is the major challenge in the implementation of computer-based programs for diagnostic advice in medicine. We here present an epistemological model of diagnosis with the ultimate goal of defining a high-level language for cognitive and computational primitives. The diagnostic task proceeds through three different phases: hypotheses generation, hypotheses testing and hypotheses closure. Hypotheses generation has the inferential form of abduction (from findings to hypotheses) constrained under the criterion of plausibility. Hypotheses testing is achieved by a deductive inference (from generated hypotheses to expected findings), followed by an eliminative induction, constrained under the criterion of covering, which matches expected findings against patient's findings to select the best explanation. Hypotheses closure is a deductive-inductive type of inference very similar to the inferences operating in hypotheses testing. In this case induction matches the consequences of the generated hypotheses against the patient's characteristics or preferences under the criterion of utility. By using the language exploited in this epistemological model, it is possible to describe the cognitive tasks underlying the most influential knowledge-based diagnostic systems.

NEOANEMIA: a knowledge-based system emulating diagnostic reasoning.

Medical diagnosis can be modeled in terms of the classical notions of abduction, deduction, and induction. Abduction is making a preliminary guess that allows one to establish a set of plausible diagnostic hypotheses, followed by deduction for exploring their consequences and induction for testing the hypotheses with available patient data or for planning the acquisition of new data. Such a description of diagnostic reasoning at a knowledge level helps the construction of an expert system by fashioning the adopted expert system building tool to reflect the structure of the problem rather than by fitting the problem to the tool. To this aim, reasoning strategies need to be represented abstractly, separate from medical facts and relations, to make the design more transparent and explainable.

Structural changes of the exocrine pancreas in a patient with cholecystolithiasis.

The exocrine pancreas has been studied histologically, morphometrically, and ultrastructurally in a patient with cholecystolithiasis in comparison with three control patients free from gastrointestinal or pancreatic diseases. In the gallstone-bearing patient, acinar cells undergo a significant increase in the average cell area and average zymogenic area (i.e., the portion of acinar cell cytoplasm occupied by zymogen granules). In addition, these cells showed cytological signs of enhanced synthesis of secretory proteins and increased formation and release of zymogen granules. The findings concerning centroacinar/ductular cells are consistent with a significant increase in their number and average cell area that is associated with ultrastructural signs of enhanced functional activity.

The exocrine pancreas in patients with hyperinsulinemic hypoglycemia. A morphometrical and ultrastructural study.

The exocrine pancreas has been studied morphometrically and ultrastructurally in 12 patients with insulin-producing tumors in comparison with control patients free from gastrointestinal or pancreatic diseases and with normal glucose homeostasis. Light microscopical examination and morphometrical data revealed that in the insulinoma-bearing patients acinar cells undergo a marked and significant decrease in zymogen granule content, together with a slight reduction in the mean cell area. Such changes were accompanied by ultrastructural features indicating increased production and exocytosis of zymogen granules. The findings concerning centroacinar/ductular cells are consistent with an increase in their number and mean cell area, and an enhancement of their functional activity. In synthesis, both the enzyme- and bicarbonate-secreting cells appear to be greatly stimulated in conditions of chronic hyperinsulinemic hypoglycemia owing to the presence of insulinomas.

[Regression of left ventricular hypertrophy in obese hypertensive patients treated with diet and pharmacologic therapy]. / Regressione dell'ipertrofia ventricolare sinistra in ipertesi obesi trattati con terapia farmacologica e dietetica.

Thirty-five obese (Body Mass Index: BMI > 30) hypertensive (diastolic blood pressure > 100 mmHg) patients were studied for 6 months. 18 patients (10 males, mean age 52 +/- 6 years) were treated with captopril 50 mg b.i.d. (Group 1); 17 patients, matched by age, sex and BMI were treated with captopril 50 mg b.i.d. and hypocaloric diet (Group 2). During follow-up a good control of blood pressure levels (< 150/90 mmHg) and a significant reduction in body weight (> 10%) were achieved in all patients of Group 2. Left heart anatomy was accessed by 2D guided M-mode echocardiogram before starting treatment and after 6 months. In Group 1 Interventricular Septal Thickness (ST), Posterior Wall Thickness (PWT) and Left Ventricular Mass (LVM) decreased significantly (p < 0.01). In Group 2 not only ST, PWT and LVM decreased significantly (p < 0.01 for ST and PWT, p < 0.001 for LVM), but also left atrial dimension (p < 0.05) and left ventricular diastolic dimension (p < 0.01). The percent reduction in AD, LVDD and LVM was significantly higher (p < 0.01) in Group 2. In obese hypertensives relevant weight loss can improve the effect of captopril treatment on left ventricular hypertrophy; the decrease of AD and LVDD is probably secondary to a reduction of the volume overload present in obese patients.