Aliment Pharmacol Ther 2011; 33: 1162–1172
Summary
Background Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma and the identification of the ...predictors of response to antiviral therapy is an important clinical issue.
Aim To determine the independent contribution of factors including IL28B polymorphisms, IFN‐gamma inducible protein‐10 (IP‐10) levels and the homeostasis model assessment of insulin resistance (HOMA‐IR) score in predicting response to therapy in chronic hepatitis C (CHC).
Methods Multivariate analysis of factors predicting rapid (RVR) and sustained (SVR) virological response in 280 consecutive, treatment‐naive CHC patients treated with peginterferon alpha and ribavirin in a prospective multicentre study.
Results Independent predictors of RVR were HCV RNA <400 000 IU/mL (OR 11.37; 95% CI 3.03–42.6), rs12980275 AA (OR 7.09; 1.97–25.56) and IP‐10 (OR 0.04; 0.003–0.56) in HCV genotype 1 patients and lower baseline γ‐glutamyl‐transferase levels (OR = 0.02; 0.0009–0.31) in HCV genotype 3 patients. Independent predictors of SVR were rs12980275 AA (OR 9.68; 3.44–27.18), age <40 years (OR = 4.79; 1.50–15.34) and HCV RNA <400 000 IU/mL (OR 2.74; 1.03–7.27) in HCV genotype 1 patients and rs12980275 AA (OR = 6.26; 1.98–19.74) and age <40 years (OR 5.37; 1.54–18.75) in the 88 HCV genotype 1 patients without a RVR. RVR was by itself predictive of SVR in HCV genotype 1 patients (OR 33.0; 4.06–268.32) and the only independent predictor of SVR in HCV genotype 2 (OR 9.0, 1.72–46.99) or genotype 3 patients (OR 7.8, 1.43–42.67).
Conclusions In HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP‐10 independently predict RVR. The combination of IL28B polymorphisms, HCV RNA level and age may yield more accurate pre‐treatment prediction of SVR. HOMA‐IR score is not associated with viral response.
•Among the choices for surgical treatment the most commonly used implants are the locking-compression plate and the intramedullary nailing.•The authors performed a clinical and radiographic follow-up ...in patients underwent antegrade intramedullary blocked nailing for proximal or diaphyseal humeral fractures.•Intramedullary nailing with a straight nail of the humerus shows good clinical and radiographic outcomes at 18 months of follow up.
Humerus fractures are frequent, accounting for about 3-4% of all fractures in adults. Treatment for fractures of the diaphyseal and proximal meta-epiphyseal regions remains controversial: there is no unanimity in the scientific community about the superiority of surgical treatment over non-surgical treatment and which is the best between possible surgical treatments. Among the choices for surgical treatment the most commonly used implants are the locking-compression plate and the intramedullary nailing. The purpose of this study was to perform a clinical and radiographic follow-up in patients who underwent surgical procedures for reduction and osteosynthesis of proximal or diaphyseal humeral fractures by means of anterograde intramedullary nailing with a straight-shaped nail.
A clinical and radiographic follow-up was performed in 56 patients who underwent surgical procedures for reduction and osteosynthesis of proximal or diaphyseal humeral fractures by means of antegrade intramedullary nailing using Synthes MultiLoc® system. Clinical data were collected using subjective quality of life assessment forms (SF12-v2), quality of life related to specific disabilities assessment forms (Quick-DASH, ASES score, WORC) and objective functional assessment forms (Constant-Murley score). The radiographic Follow-Up was performed at 30, 90 and 180 days from the date of the surgery.
Almost all patients were able to return to a satisfactory quality of life, comparable with the one before the traumatic episode. The functional results were assessed as excellent or good with almost complete recovery of the range of motion and moderate recovery of strength. The residual pain encountered was moderate or zero. The average QuickDASH score was 17.7 ± 4.3 (range 9.1 - 27.3). The average ASES score was 73.8 ± 8.1 (range 58.3 - 88.3). The average WORC score was 543.3 ± 100 74% ± 4.8% (range 310 - 740). The mean Constant-Murley score was 69.6 ± 4.6 (range 61 - 84). All patients had a fair or good consolidation of the fracture on radiographic examinations. The calculated RUST score was 4.2 ± 0.4 (range 4-5) 30 days after surgery, 6.1 ± 0.9 (range 4- 8) 90 days after surgery and 9.8 ± 1.5 (range 7-12) to 180 days after surgery. No major complications were found.
Treatment of the diaphyseal and proximal meta-epiphyseal humeral fractures with antegrade intramedullary nail provides excellent subjective and objective clinical results and good radiographic results. However, clinical studies with larger number of patients and longer follow-up are necessary.
Display omitted
To use Multi-Criteria Decision Analysis (MCDA) to determine weights for eleven criteria in order to prioritize COVID-19 non-critical patients for admission to hospital in healthcare ...settings with limited resources.
The MCDA was applied in two main steps: specification of criteria for prioritizing COVID-19 patients (and levels within each criterion); and determination of weights for the criteria based on experts’ knowledge and experience in managing COVID-19 patients, via an online survey. Criteria were selected based on available COVID-19 evidence with a focus on low- and middle-income countries (LMICs).
The most important criteria (mean weights, summing to 100%) are: PaO2 (16.3%); peripheral O2 saturation (15.9%); chest X-ray (14.1%); Modified Early Warning Score-MEWS (11.4%); respiratory rate (9.5%); comorbidities (6.5%); living with vulnerable people (6.4%); body mass index (5.6%); duration of symptoms before hospital evaluation (5.4%); CRP (5.1%); and age (3.8%).
At the beginning of a new pandemic, when evidence for disease predictors is limited or unavailable and effective national contingency plans are difficult to establish, the MCDA prioritization model could play a pivotal role in improving the response of health systems.
Isolated apophyseal avulsion of the greater trochanter is a rare condition in the paediatric population, frequently related to avascular necrosis of the femoral head. Since there are few cases in the ...literature, there is no consensus regarding the best treatment of this injury. Our study describes the case of a 9-year-old patient with an avulsion of the right greater trochanter. A minimally invasive osteosynthesis was performed, achieving complete clinical and radiographic healing of the patient and no long-term complications after four years.
Background
Elevated fasting plasma glucose has been associated with increased risk for development of type 2 diabetes (T2D). The balance between glucokinase (GCK) and glucose-6-phosphate catalytic ...subunit 2 (G6PC2) activity are involved in glucose homeostasis through glycolytic flux, and subsequent insulin secretion.
Aim
In this study, we evaluated the association between the genetic variability of
G6PC2
and
GCK
genes and T2D-related quantitative traits.
Methods
In 794 drug-naïve, GADA-negative, newly diagnosed T2D patients (VNDS; NTC01526720) we performed: genotyping of 6 independent tag-SNPs within
GCK
gene and 5 tag-SNPs within
G6PC2
gene; euglycaemic insulin clamp to assess insulin sensitivity; OGTT to estimate beta-cell function (derivative and proportional control; DC, PC) by mathematical modeling. Genetic association analysis has been conducted using Plink software.
Results
Two SNPs within
GCK
gene (rs882019 and rs1303722) were associated to DC in opposite way (both
p
< 0.004). Two
G6PC2
variants (rs13387347 and rs560887) were associated to both parameters of insulin secretion (DC and PC) and to fasting C-peptide levels (all
p
< 0.038). Moreover, subjects carrying the A allele of rs560887 showed higher values of 2h-plasma glucose (2hPG) (
p
= 0.033). Haplotype analysis revealed that
GCK
(AACAAA) haplotype was associated to decreased fasting C-peptide levels, whereas, the most frequent haplotype of
G6PC2
(GGAAG) was associated with higher fasting C-peptide levels (
p
= 0.001), higher PC (
β
= 6.87,
p
= 0.022) and the lower 2hPG (
p
= 0.012).
Conclusion
Our findings confirmed the role of GCK and G6PC2 in regulating the pulsatility in insulin secretion thereby influencing insulin-signaling and leading to a gradual modulation in glucose levels in Italian patients with newly diagnosed T2D.
We tested the hypothesis that common genetic variability of beta-cell genes responsible for monogenic diabetes may affect beta cell function in type 2 diabetes mellitus (T2DM). We studied 794 drug- ...naïve GAD-negative patients with newly diagnosed T2DM (age: median=59 years; I.Q. range: 52-66; body mass index: 29.3 kg/m2; 26.6-32.9). Beta-cell function was assessed by state-of-art mathematical modeling of glucose/C-peptide curves during a 240’-300’ frequently sampled oral glucose tolerance test, to provide the beta-cell responses to the rate of increase in glucose concentration (derivative control: DC) and to glucose concentration (proportional control: PC). Forty-two single nucleotide polymorphism (SNPs), selected to cover over 90% of common genetic variability, were genotyped in nine monogenic diabetes genes: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, KCNJ11 and ABCC8. Allelic variants of four SNPs (rs1303722 and rs882019 of GCK, rs7310409 of HNF1A and rs5219 of KCNJ11) were significantly associated with DC of beta-cell secretion (all P < 0.036). Allelic variants of four other SNPs (rs2868094 and rs6031544 of HNF4A, and rs1801262 and rs12053195 of NEUROD1) were associated with PC of beta-cell secretion (P < 0.02). In multivariate models, GCK, HNF1A and KCNJ11 SNPs explained 2.5% of the DC variability of beta-cell secretion, whereas HNF4A and NEUROD1 SNPs explained 3.6% of the PC variability of beta-cell secretion. We conclude that common variability of monogenic diabetes genes is significantly associated with an impaired beta-cell function in patients with newly diagnosed T2DM; thereby, these genes might be targeted by specific treatments in T2DM.
Sub-trochanteric fractures are among the most challenging for trauma surgeons. The purpose of this study was to analyze our own experience about subtrochanteric fractures. We focused on functional ...and radiographic outcomes after intramedullary locked nail fixation with or without cerclage assist.
A retrospective analysis on subtrochanteric fractures managed from January 2016 to April 2021 was conducted. Patients treated by closed reduction and intramedullary nail fixation were enrolled in Group A, while Group B included those patients who underwent wire-assisted intramedullary nail fixation. All patients performed clinical and radiological follow-up and complications were analyzed. The significance was established for a value of p < 0.05.
80 patients were included in the present study. The mean age was 74.2 (+/-19.2) years. The mean surgical time was 84.7 (+/-24.6) and 254.7 (+/-80.2) minutes in Group A and Group B, respectively. The mean blood loss was 87.3 (+/-18.3) ml in Group A and 224.4 (+/-37.8) ml in Group B. Quality of reduction was mainly superior in Group B. The mean time of union was 4.2 (+/-1.4) months in Group A and 3.4 (+/-2.1) months in Group B. Statistical differences were observed in Visual Analogue Scale (VAS) and in the Short Form 12 (SF-12) after 6 and 12 months of follow-up with better results in Group B. The complication rate was 18.2% in Group A and 12.2% in Group B.
We recommend the use of wires when acceptable closed reduction cannot be obtained because its use may be useful for medial wall stability. For elderly patients, closed reduction may be more appropriate as the quality of life and functional recovery between the two methods is almost overlapped.
The neurofilament light chain (NF-L) is a major constituent of intermediate filaments and plays a pivotal function in the assembly and maintenance of axonal cytoskeleton. Mutations in the NF-L gene ...(NEFL) cause autosomal dominant neuropathies that are classified either as axonal Charcot–Marie–Tooth (CMT) type 2E (CMT2E) or demyelinating CMT type 1F (CMT1F). The pathophysiological bases of the disorder(s) are elusive. We performed a mutational analysis of NEFL in a series of 177 index cases with CMT and without mutations in the genes for peripheral myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22) and connexin 32 (GJB1); the motor nerve conduction velocity (MNCV) at the median nerve was below 38 m/s in 76 cases and above 38 m/s in 101. We identified five new pedigrees with four mutations in the head and rod domains of NF-L, including a novel Leu268Pro substitution and a novel del322Cys_326Asn deletion. Several examined affected members exhibited marked variability in the severity of disease and age at onset. Nerve conduction alterations were consistent with an axonal neuropathy often associated with demyelinating features, such as prolonged distal latencies (DL). Pathological examination of sural nerve biopsies in the probands detected in four cases a chronic axonal neuropathy dominated by focal accumulations of NF with axonal swellings (giant axons) and significant secondary demyelination; in the fifth case no NFs accumulations were evident but many myelinated fibres consisted exclusively of microtubules with few or absent NF. The pathological phenotype correlated with the pattern of nerve conduction alterations and indicated that NEFL mutations cause a profound alteration of the cytoskeleton possibly related to defective targeting of NF.
We investigated cross-sectionally whether the type 2 diabetes (T2DM) risk alleles of rs1801282 (
PPARG2
) and rs4607103 (
ADAMTS9
) were associated with T2DM and/or insulin sensitivity (IS) and beta ...cell function (βF) in Italians without and with newly diagnosed T2DM. In 676 nondiabetic subjects (336 NGR and 340 IGR) from the GENFIEV study and in 597 patients from the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS), we (1) genotyped rs1801282 and rs4607103, (2) assessed βF by C-peptide/glucose modeling after OGTT, and (3) assessed IS by HOMA-IR in both studies and by euglycemic insulin clamp in VNDS only. Logistic, linear, and two-stage least squares regression analyses were used to test (a) genetic associations with T2DM and with pathophysiological phenotypes, (b) causal relationships of the latter ones with T2DM by a Mendelian randomization design. Both SNPs were associated with T2DM. The rs4607103 risk allele was associated to impaired βF (
p
< 0.01) in the GENFIEV study and in both cohorts combined. The rs1801282 genotype was associated with IS both in the GENFIEV study (
p
< 0.03) and in the VNDS (
p
< 0.03), whereas rs4607103 did so in the VNDS only (
p
= 0.01). In a Mendelian randomization design, both HOMA-IR (instrumental variables: rs1801282, rs4607103) and βF (instrumental variable: rs4607103) were related to T2DM (
p
< 0.03–0.01 and
p
< 0.03, respectively).
PPARG2
and
ADAMTS9
variants are both associated with T2DM and with insulin resistance, whereas only
ADAMTS9
may be related to βF. Thus, at least in Italians, they may be considered
bona fide
“insulin resistance genes”.
Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of familial vascular dementia, is caused by mutations of the NOTCH3 ...gene. Approximately two hundred pathogenic mutations have been reported within five exons (exons 3, 4, 6, 11 and 19) which accounted for 78% of known mutations in worldwide series. We reported twenty-one NOTCH3 pathogenic mutations (including five novel ones) identified in 53 index Italian patients. Exons 4 (28%), 7 (21%) and 19 (24%) were the most frequently involved. To dissect genetic heterogeneity, we analyzed five haplotyped tagging single nucleotide polymorphisms (rs1044009, rs4809030, rs10426042, rs10423702 and rs3815188) in 95 patients, 39 unaffected pedigree members and 50 healthy controls. SNPs were analyzed using the Illumina VeraCode Universal Capture Beads technology by Allele Specific Primer Extension (ASPE). We identified ten different haplotypes named H1–H10; H1 was the most common haplotype in patients and controls and it was associated with at least twelve out of the twenty-one mutations. Detected mutations were not associated to specific haplotypes while genotyping was compatible with a possible founder effect for the novel p.S396C mutation which clustered in a restricted geographical area of northeast Italy. The results added on to the genetic heterogeneity of CADASIL and emphasized difficulties in designing algorithms for molecular diagnosis.
PDF
