Predisposing and protective factors influencing suicide ideation, attempt, and death in patients accessing substance use treatment: a systematic review and meta-analysis protocol.

BACKGROUND: The lifetime risk of suicide in patients with substance use disorder is five to ten times the risk in the general population. Critically, up to 19% of patients continue to think about and attempt suicide even after accessing treatment. Therefore, suicidality represents a significant clinical concern in patients struggling with substance use that warrants careful investigation of the factors involved. While most previous research has relied on limited cross-sectional designs, a growing number of prospective studies are improving our understanding of the factors involved. However, a systematic study of these factors has not yet been conducted. METHODS: The primary objective of this review and possible meta-analysis will be to identify key risk and protective factors for suicide ideation, attempt, and death in patients accessing substance use treatment, guided by current models of suicide. Secondary and tertiary objectives will be to obtain pooled effect sizes for the factors identified and to disaggregate factors for suicidality before and after treatment, and for suicidal thought versus action. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we will conduct an electronic search of the literature using the databases Embase, Medline, PsycINFO, and Web of Science. Two authors will independently screen studies based on pre-specified inclusion and exclusion criteria, extract relevant data, and assess study quality. Observational and randomized-controlled studies will be included, whereas case-studies and reviews will be excluded. We will extract data on risk and protective factors associated with suicide ideation, attempt (odds or risk ratios), and death (hazard ratio). Given sufficient data (> 5 studies), we will calculate pooled effects using comprehensive meta-analysis. DISCUSSION: This systematic review will contribute to our knowledge of risk and protective factors for suicidality in patients before and after treatment. Understanding these factors will help define areas of research for further investigation to ultimately inform risk assessment and prevention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (reference number: CRD42018076260).

Low abdominal contribution to breathing as daytime predictor of nocturnal desaturation in adolescents and young adults with Duchenne Muscular Dystrophy.

In the respiratory management of DMD patients it is still under debate what parameter should indicate the correct timing for institution of nocturnal non-invasive ventilation (NIV), in addition to forced vital capacity, which is generally considered as a prognostic marker of disease progression. The aim of this study was to determine if volume variations of rib cage and abdominal compartments measured by Opto-Electronic Plethysmography can be helpful to distinguish between those patients who are in the early stages of nocturnal oxygen desaturation development and those who do not yet. Pulmonary function, abdominal contribution to tidal volume and to inspiratory capacity (%Abd IC) and a set of breathing pattern indexes were assessed in 40 DMD patients older than 14 years and not yet under nocturnal NIV. ROC analysis revealed that among all the considered parameters, %Abd IC in supine position was the best discriminator between DeSat (at least 10% of the night time with SpO(2) < 95%) and NonDeSat patients, providing an area under the curve with 95%CI equal to 0.752. In conclusion, in adolescents and adults DMD patients who present either no sign or only mild nocturnal oxygen desaturation, a reduced abdominal contribution to inspiratory capacity is a marker of the onset of diaphragm weakness and should be considered to identify the correct timing for the institution of nocturnal NIV.

Respiratory pattern in an adult population of dystrophic patients.

We studied respiratory function and Chest Wall kinematics in a large population of adult patients affected by slow course muscular dystrophies such as Limb-Girdle Muscular Dystrophy (LGMD, n=38), Becker Muscular Dystrophy (BMD, n=20) and Facio-Scapulo Humeral Dystrophy (FSHD, n=30), through standard spirometry and through the Optoelectronic Plethysmography, to measure the thoraco-abdominal motion during Quiet Breathing and Slow Vital Capacity maneuvers. Within the restrictive pulmonary syndrome characterizing LGMD and FSHD, several different thoraco-abdominal patterns compared to those of healthy subjects were present in the more advanced stages of the disease. These differences were present in the seated position, during the execution of a maximal maneuver such as Slow Vital Capacity. A global respiratory (both inspiratory and expiratory) muscle involvement was more pronounced in the LGMD and FSHD than in the BMD patients, and a significant reduction of abdominal contribution in wheelchair bound patients was observed. In conclusion, OEP technique is able to reveal mild initial modifications in the respiratory muscles in FSHD and LGMD patients, which could be helpful for functional and new therapeutic strategy evaluation.

Quantitative evaluation protocol for upper limb motor coordination analysis in patients with ataxia.

Objective and quantitative measurement is crucial in the definition of functional impairment and in the tracking of disease progress over time of patients affected by progressive pathologies, such as ataxia. A new experimental procedure for the quantitative description of upper limb movement and coordination analysis was developed by the integration of an optoelectronic system and dedicated electronic board with four visual and pressure stimuli. 20 passive retroreflective markers were placed on the subject's body and two types pointing tests were defined: in the first one, the subjects were asked to reach with the index finger five consecutive times each of the three targets ("repetitive test"), and in the second one, the subjects were asked to randomly reach the targets with the index finger ("random test"). The preliminary results showed that patients affected by ataxia took more time with a less smooth finger tip movement to perform the reaching tests when compared to healthy subjects. The velocity was lower and its profile was more irregular in ataxic subjects. The new developed experimental procedure seems to be very promising in the quantitative description of upper limb movements of pathological and healthy subjects and it seems to be able to distinguish the impairments due to different levels of ataxia.

The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K.

BACKGROUND: Mutations in GDAP1 associate with demyelinating (CMT4A) and axonal (CMT2K) forms of CMT. While CMT4A shows recessive inheritance, CMT2K can present with either recessive (AR-CMT2K) or dominant segregation pattern (AD-CMT2K), the latter being characterised by milder phenotypes and later onset. The majority of the GDAP1 mutations are associated with CMT4A and AR-CMT2K, with only four heterozygous mutations identified in AD-CMT2K. METHODS: We screened GDAP1 gene in a series of 43 index patients, 39 with CMT2 and 4 with intermediate CMT, with sporadic and familial occurrence of the disease. RESULTS: Three novel mutations were identified in three families with dominant segregation of the disease: two missense changes, p.Arg226Ser and p.Ser34Cys, affecting the GST domain of the GDAP1 protein and a novel deletion (c.23delAG) leading to early truncation of the protein upstream the GST domain. Wide variability in clinical presentation is shared by all three families mostly in terms of age at onset and disease severity. A rare variant p.Gly269Arg, located within the GST domain, apparently acts as phenotype modulator in the family carrying the deletion. CONCLUSION: The results obtained reveal a GDAP1 mutation frequency of 27% in the dominant families analysed, a figure still unreported for this gene, thus suggesting that GDAP1 involvement in dominant CMT2 might be higher than expected.

Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction.

BACKGROUND: The axonal forms of Charcot-Marie-Tooth (CMT2) disease are a clinically and genetically heterogeneous group of disorders. Mitofusin 2 gene (MFN2) mutations are the most common cause of CMT2. Complex phenotypes have been described in association with MFN2 gene mutations, including CMT2 with pyramidal features (hereditary motor and sensory neuropathy [HSMN V]) and CMT2 with optic atrophy (HMSN VI). OBJECTIVE: To report on the clinical, neurophysiologic, and neuropathologic features of an Italian family with a novel MFN2 gene mutation and investigate brain functional parameters using magnetic resonance spectroscopy (MRS). METHODS: Three family members, a father and his two sons, were affected by peripheral neuropathy, cognitive impairment, and poor nocturnal vision (also optic neuropathy in one case). A member of this family also showed spastic paraparesis. The MFN2 gene sequence was analyzed. A sural nerve biopsy as well as brain (1)H-MRS and (31)P-MRS were evaluated in two patients. RESULTS: Affected family members carried a novel MFN2 missense mutation, namely R104W, located within the critical GTPase domain of the protein which affects a highly conserved amino acid position. Sural nerve biopsies showed a normal mitochondrial network, particularly at the nodes of Ranvier, upon electron microscopy examination. A significant defect of high energy phosphates (HEPs) in the visual cortex was observed at rest by (31)P-MRS in the adult proband, while his son showed a defective recovery of HEPs after stimulation of the visual cortex. CONCLUSION: Cognitive impairment may be another feature of the MFN2-related phenotype. The widespread peripheral and CNS involvement, as well as the neurosensorial defects, underline the similarities among MFN2-related and primary mitochondrial disorders.

Nuclear reprogramming and adult stem cell potential.

Cell-based therapy may represent a new strategy to treat a vast array of clinical disorders including neurodegenerative diseases. Recent observations indicate that adult somatic stem cells have the capacity to contribute to the regeneration of different tissues, suggesting that differentiative restrictions are not completely irreversible and can be reprogrammed. Cell fusion might account for some changed phenotype of adult cells but it seems to be biologically irrelevant for its extreme rarity. Other experimental evidences are compatible with the hypothesis of wide multipotency of well-defined stem cell populations, but also with transdifferentiation and/or dedifferentiation. Further studies on nuclear reprogramming mechanisms are necessary to fulfil the promise for developing autologous cellular therapies.

A CAV3 microdeletion differentially affects skeletal muscle and myocardium.

BACKGROUND: Caveolin-3 is the muscle-specific protein product of the caveolin gene family and an integral membrane component of caveolae. Mutations in the gene encoding caveolin-3 (CAV3) underlie four distinct disorders of skeletal muscle: the autosomal dominant form of limb-girdle muscular dystrophy type 1C (LGMD-1C), rippling muscle disease (RMD), sporadic and familial forms of hyperCKemia, and distal myopathy. OBJECTIVE: To characterize a multigenerational Italian family affected by an autosomal dominant myopathic disorder and to assess the expression of caveolin-3, dystrophin, dystrophin-associated glycoproteins, and neuronal nitric oxide synthase in the myocardium of an affected patient. METHODS: Clinical analysis involved 15 family members. Skeletal muscle expression of sarcolemmal proteins was evaluated by immunohistochemistry and western blot analysis in three affected individuals. Caveolar structures were analyzed through electron microscopy in muscle biopsies and in one heart biopsy. RESULTS: CAV3 genetic analysis showed a heterozygous 3-bp microdeletion (328-330del) in affected individuals, resulting in the loss of a phenylalanine (Phe97del) in the transmembrane domain. In the skeletal muscle, the mutation was associated with severe caveolin-3 deficiency and caveolar disorganization, whereas the expression of the other analyzed muscle proteins was unaltered. Remarkably, caveolin-3 was expressed in myocardium at a level corresponding to about 60% of that of control individuals and was correctly localized at the myocardial cell membranes, with preservation of cardiac myofiber caveolar structures. Clinical analysis revealed the concomitant presence in this family of the following phenotypes: RMD, LGMD, and hyperCKemia. CONCLUSIONS: Intrafamilial phenotypic heterogeneity is associated with caveolin-3 Phe97 microdeletion. The molecular network interacting with caveolin-3 in skeletal muscle and heart may differ.

Cognitive assessment in primary biliary cirrhosis: a case-control study.

OBJECTIVES: Primary biliary cirrhosis (PBC) patients frequently complain of fatigue and loss of memory. The aim of this study was to evaluate the mental performance and the neuropsychological assessment in patients with PBC. METHODS: A case-control study was performed that included 36 PBC patients (34 female, two male, mean age 55 yrs, 11 with stage II, 16 with stage III, and nine with stage IV disease) and 36 sex and age-matched controls with rheumatoid arthritis. A preliminary routine neurological examination failed to show any abnormality in each patient, including signs of encephalopathy. A battery of neuropsychological tests was administered to each subject, including: the Global Deterioration Scale; the Mini Mental State Examination; Buschke test; Gatterer's test; the Wechsler Memory Scale; the Blessed-Roth memory test; and the Clifton Assessment Schedule. RESULTS: The overall score for each test was not statistically different in PBC patients compared with rheumatoid arthritis patients, except for the Global Deterioration Scale and the Clifton Assessment Schedule; the performance was significantly poorer for these measures in PBC patients compared with rheumatoid arthritis patients. In both groups no correlation was found between the score of each test and age and/or duration of the disease. However, in the PBC group the score of BR was negatively correlated with the histological stage (p < 0.0025). CONCLUSION: The global mental status is not altered in PBC, but early changes in orientation and in personal memory are present in cirrhotic stage.

Efficacy and safety of the stepped care medical treatment of ascites in liver cirrhosis: a randomized controlled clinical trial comparing two diets with different sodium content.

In order to clarify debated issues of the medical treatment of ascites in cirrhosis--the usefulness of a low sodium diet and washout period preceding diuretic administration, maximal dosage of antimineralocorticoid to be reached before the addition of a loop diuretic, identifications of factors influencing treatment efficacy--115 hospitalized patients with non-azotemic cirrhosis and ascites were recruited and randomized to receive a diet providing either 40 or 120 mmol of sodium daily. After a washout period from the outpatient diuretic regimen for 7 days (Step 1), increasing dosages of K-canrenoate (200 mg/day every 4th day up to 600 mg) were administered to patients not undergoing spontaneous diuresis (Step 2). Upon the failure of Step 2, K-canrenoate (400 mg/day) and furosemide at increasing dosage (25-50-100 mg every other day) were given (Step 3). Nine percent of patients underwent spontaneous diuresis, and 77% developed a negative sodium balance by the end of Step 2 (69% with a dosage of K-canrenoate < or = 400 mg/day) and 93% by the end of Step 3. Two patients were withdrawn from the protocol due to diuretic side-effects. Univariate analysis showed that the type of diet did not influence the response to treatment. The washout period led to a significant increase in endogenous creatinine clearance; natremia significantly rose in hyponatremic patients. Multivariate analysis showed that creatinine clearance and plasma aldosterone were independent predictive factors of the response to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Concentrated ascitic fluid reinfusion after cascade filtration in tense ascites.

A new method for concentrated ascitic fluid reinfusion using a double ultrafiltration device is reported as 22 procedures in 20 cirrhotic patients (6 females, 14 males; median age 55 years, range 33-69) with tense, refractory ascites. Eight of the 20 patients had elevated creatinine levels. The mean time for each procedure was 189 +/- 82 min, during which a mean of 7.7 liters (1.3-13.3) of ultrafiltered ascitic fluid was removed and 613 ml (140-1700) of concentrated ascitic fluid rich in albumin (mean: 60 g, range 14-175) was reinfused. The procedure resulted in a mean weight loss of 8.1 kg (2.2-14.0) and a mean increase of 163 ml in urine output (24 hr). A reduction in the serum creatinine level (P < 0.05) and an increase in the plasma atrial natriuretic factor level (P < 0.02) 24 hr after reinfusion, while no changes in serum albumin, plasma and urinary electrolytes, plasma renin activity, aldosterone, and antidiuretic hormone levels were noted. Although minor evidence for a disturbance in coagulation was observed, there were no episodes of clinical bleeding. Four patients (20%) had transient chills or fever. Based upon this experience, it can be concluded that reinfusion of cascade filtered and concentrated ascitic fluid is a rapid, safe, and effective treatment for patients with tense ascites; it appears to have less side effects than more traditional methods and importantly does not require administration of heterologous plasma derivatives.