A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians

CD36 is a class B scavenger receptor recognizing a variety of ligands including long-chain fatty acids and modified LDL. We investigated whether genetic variability at this locus is a determinant of free fatty acid (FFA) plasma levels and risk of coronary artery disease (CAD) in Caucasians. Typing of 21 polymorphic markers, evenly spanning the CD36 gene, revealed two linkage disequilibrium (LD) blocks that could be tagged by five polymorphisms (-33137A>G, -31118G>A, 25444G>A, 27645del>ins and 30294G>C). In 585 non-diabetic individuals of Caucasian origin, the 30294G>C polymorphism was significantly associated with FFA levels (P = 0.02)--an effect that was especially visible among men (P = 0.009). A similar association was observed in this gender at -33137 (P = 0.008) and -31118 (P = 0.028). When the five tag polymorphisms were considered together, men carrying the AGGIG haplotype had 31% higher FFA (P = 0.0002) and 20% higher triglycerides (P = 0.025) than non-carriers. The same haplotype was associated with increased risk of CAD in 197 type 2 diabetic individuals from the US (OR = 2.3, 95% CI 1.2-4.2). A similar tendency was observed in a group of 321 type 2 diabetic individuals from Italy (OR = 1.4, 0.9-2.3), resulting in an overall relative risk of 1.6 (1.1-2.3, P = 0.015) in the two populations considered together. By targeted resequencing, we identified a common variant in the CD36 promoter that is in strong LD with the AGGIG haplotype and could be partly responsible for these findings. In conclusion, this comprehensive study of CD36 variability indicates that the common polymorphisms at this locus modulate lipid metabolism and cardiovascular risk in Caucasians.     

Predictive value of intact parathyroid hormone measurement during surgery for renal hyperparathyroidism

Background and aims In contrast to that in patients with primary hyperparathyroidism, the value of intraoperative intact parathyroid hormone (iPTH) measurement is still unclear in patients with renal hyperparathyroidism and was, therefore, evaluated in a large cohort of patients.Patients Intraoperative iPTH measurement was performed in 153 patients with renal hyperparathyroidism (129 with terminal renal failure and 24 with functioning kidney graft). Subtotal and total parathyroidectomy were performed in 123 and 13 patients, respectively, during initial surgery. In patients with recurrent disease (17), the respective hyperfunctioning tissue was removed. Intraoperative blood samples were obtained by puncture of the internal jugular vein before preparation of the parathyroids (PTH₀) and 15 min after parathyroidectomy (PTH₁₅). iPTH was measured with the Elecsys 2010 system. Postoperative iPTH levels (PTH_post) were determined at postoperative days 1 to 3 and at week 2. Patients were arbitrarily divided in four groups according to the postoperative iPTH values: 0–25 pg/ml (group 1), 26–65 pg/ml (group 2), 66–150 pg/ml (group 3) and more than 150 pg/ml (group 4).Results The mean PTH₀ value was 869±57 pg/ml, which decreased to 167±15 pg/ml at PTH₁₅. The mean relative PTH₁₅ value was 21.6±1.7%. Postoperatively, iPTH decreased to 42±9 pg/ml. The postoperative iPTH value of the 129 patients with terminal renal failure was 25 pg/ml or less in 99 patients, 26–65 pg/ml in 11 patients, 66–150 pg/ml in eight patients and higher than 150 pg/ml in 11 patients. Two successive criteria of iPTH decrease were used: first, a PTH₁₅ of 150 pg/ml or, second, a relative PTH₁₅ of 30% less was used. Fifteen patients did not fulfil both criteria. In 13 of them (86.7%) iPTH_post was higher than 65 pg (true failure to decline). Of 114 patients who fulfilled the criteria, 108 (94.7%) had normal postoperative iPTH values (true decline). Absolute PTH₁₅ values of less than 150 pg/ml predicted normal postoperative iPTH levels in 77 of 78 patients.Conclusion A PTH₁₅ value of 150 pg/ml or less predicts operative success in patients with renal failure in 98.7% of cases, independently of the relative decay. In contrast, if the relative PTH₁₅ is higher than 30%, high postoperative PTH values are predicted with a probability of 86.7%. Although there remain some borderline cases, intraoperative iPTH measurement is accurate and also can be useful in patients with renal hyperparathyroidism.The paper was presented at the first constitutive meeting of the European Society of Endocrine Surgeons (ESES) in Pisa, Italy, on 14–15 May 2004     

(Pro)renin receptor peptide inhibitor "handle-region" peptide does not affect hypertensive nephrosclerosis in Goldblatt rats

The (pro)renin receptor [(P)RR], a new component the renin-angiotensin system, was cloned recently. The (P)RR promotes direct mitogen-activated protein kinase signaling and nonproteolytic prorenin activation. We investigated the role of a (P)RR blocker, a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP), on target organ damage in renovascular hypertensive 2-kidney, 1-clip (2K1C) rats. Vehicle-treated 2K1C rats were compared with HRP-treated 2K1C rats (3.5 mug/kg per day) and sham-operated controls. Vehicle-treated 2K1C rats developed hypertension (186+/-17 mm Hg), cardiac hypertrophy (3.16+/-0.16 mg/g), renal inflammation, fibrosis, vascular, and tubular damage. Chronic HRP treatment did not affect blood pressure (194+/-15 mm Hg), cardiac hypertrophy (2.97+/-0.11 mg/g), or renal damage. Furthermore, we investigated the renal renin and (P)RR expression. The clipped kidney of 2K1C and HRP-treated 2K1C rats showed a higher renin expression and juxtaglomerular index compared with sham-operated kidneys. The unclipped kidney showed suppressed renin expression. In contrast, (P)RR mRNA expression was not altered in any group. Plasma renin activity and aldosterone were increased in 2K1C rats compared with sham controls. HRP-treated 2K1C rats tended to lower plasma renin activity but showed similar aldosterone levels as vehicle-treated 2K1C rats. Our results indicate that blockade of the (P)RR with HRP does not improve target organ damage in renovascular hypertensive rats.     

Perceptual Changes in the Peri‐Implant Soft Tissues Assessed by Directional Cutaneous Kinaesthesia and Graphaesthesia: A Prospective Study

Background: The innervation of skin and oral mucosa plays a major physiological role in exteroception. This innervation is also clinically relevant as sensory changes occur after neurosurgical procedures. Purpose: The goal of this study was to compare the perception of mechanical stimuli applied to the buccal mucosa in the vicinity of osseointegrated oral implants with that in the controlateral dentate side. The role of the previously reported increased innervation in the peri‐implant soft tissues in the oral sensorimotor function was thus examined. Materials and Methods: Seventeen subjects with 20 implants were tested. Directional cutaneous kinaesthesia (DCK) and graphesthesia (G) were performed on the buccal side of the alveolar mucosa before and at planned intervals after implant placement. The observation was pursued until 6 months after the prosthetic rehabilitation. In each subject, the contralateral mucosa served as a control to the implant sites. Average percentages of correct responses in a four‐choice task for DCK and a three‐choice task for G were calculated. Results: Despite an intersubject variation in both the DCK and G, high intraindividual correlations were found (p < .005). The implant sites showed a significant difference toward the control sites at the four interval test for both tests. For DCK and G, the average of correct responses decreased after abutment connection (i.e., after the implant uncovering surgery) to increase afterwards to reach a level close to, but still lower than, the control sites 3 to 6 months after the prosthetic rehabilitation. Conclusion: The DCK and G are simple but reliable sensory tests that can be easily applied in the oral region. This prospective study indicates that tooth loss reduces tactile function compared with implant‐supported prostheses. The peri‐implant soft tissues could be partially involved in the osseoperception function.     

The lack of influence of IVS5-91 G>A polymorphism of the SCN1A gene on efficacy of lamotrigine in patients with focal epilepsy

ABSTRACT

Background: IVS5-91G>A (rs3812718) polymorphism of the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene has been associated with inadequate responsiveness to common antiepileptic drugs which act as sodium channel blockers. This study was performed to investigate the effect of IVS5-91G>A (rs3812718) polymorphism on lamotrigine (LTG) efficacy in a cohort of patients with non-lesional focal epilepsy taking LTG as monotherapy.

Methods: A total of 100 of patients with non-lesional focal epilepsy on LTG monotherapy was included in this prospective interventional study. After reaching a stable dose of LTG patients were followed-up for 12 consecutive months. LTG responsiveness was defined as a 75% or more reduction in seizure frequency on a stable dose of LTG. Genotyping was performed at the end of the study using standard procedures and data were correlated with clinical data.

Results: There were no significant differences in the prevalence of responsiveness to LTG between carriers of different genotypes. Average maintenance LTG doses in the responder group differed by genotype in the order AA>GA>GG, but these differences did not reach statistical significance.

Conclusion: Our data suggest lack of association between SCN1A IVS5-91G>A (rs3812718) polymorphism and response to LTG.     

Impact of vaginal and cervical colonisation/infection on preterm delivery

BACKGROUND/AIM: Preterm delivery together with insufficient body weight and death cases in newborns is the main issue in obstetrics. About 40% of preterm delivery is caused by infections. The aim of this study was to investigate whether and which bacterial infections of genital tract can be associated with preterm delivery, and depending on when diagnosis was made. METHOD: The study involved 216 pregnant women. According to pregnancy outcome, two groups were formed. The study group involved 29 pregnant women who had preterm delivery out of which nine were examined in I trimester, eight in II trimester and 12 in III trimester. The control group involved 187 pregnant women out of which 47 were examined in I trimester, 73 in II trimester and 67 in III trimester. Bacteriological examination of vaginal and cervical swabs was done in all pregnant women. Infection was diagnosed by finding bacterial antigen in cervical swabs or positive cultures of vaginal and/or cervical swabs followed by the presence of the increased number of polymorphonuclears in direct microscopic preparation. RESULTS: The results showed that in III trimester of pregnancy vaginal bacterial infection was statistically more common (p = 0.021) in women who had preterm delivery (66.7%) in relation to women who delivered in term (29.9%). In this period of gestation the increased number of polymorphonuclears in DMP of vaginal swabs is more common in the women of the study group (75%) than in the women of the control group (43.3%). Preterm delivery was registered in 16.1% women whose microbiological analyses were done in I trimester, 9.9% women in whom microbiological analyses were done in II trimester and in 15.2% pregnant women microbiologically tested in III trimester. CONCLUSION: Based on the obtained results it could be concluded that bacterial infections of genital tract and period of gestation when infection is diagnosed have influence on reducing perinatal morbidity and mortality caused by preterm delivery.     

Diagnostic approach to neurotransmitter monoamine disorders: experience from clinical,biochemical, and genetic profiles

Background and aim

To improve the diagnostic work-up of patients with diverse neurological diseases, we have elaborated specific clinical and CSF neurotransmitter patterns.

Methods

Neurotransmitter determinations in CSF from 1200 patients revealed abnormal values in 228 (19%) cases. In 54/228 (24%) patients, a final diagnosis was identified.

Results

We have reported primary (30/54, 56%) and secondary (24/54, 44%) monoamine neurotransmitter disorders. For primary deficiencies, the most frequently mutated gene was DDC (n = 9), and the others included PAH with neuropsychiatric features (n = 4), PTS (n = 5), QDPR (n = 3), SR (n = 1), and TH (n = 1). We have also identified mutations in SLC6A3, FOXG1 (n = 1 of each), MTHFR (n = 3), FOLR1, and MTHFD (n = 1 of each), for dopamine transporter, neuronal development, and folate metabolism disorders, respectively. For secondary deficiencies, we have identified POLG (n = 3), ACSF3 (n = 1), NFU1, and SDHD (n = 1 of each), playing a role in mitochondrial function. Other mutated genes included: ADAR, RNASEH2B, RNASET2, SLC7A2-IT1 A/B lncRNA, and EXOSC3 involved in nuclear and cytoplasmic metabolism; RanBP2 and CASK implicated in post-traductional and scaffolding modifications; SLC6A19 regulating amino acid transport; MTM1, KCNQ2 (n = 2), and ATP1A3 playing a role in nerve cell electrophysiological state. Chromosome abnormalities, del(8)(p23)/dup(12) (p23) (n = 1), del(6)(q21) (n = 1), dup(17)(p13.3) (n = 1), and non-genetic etiologies (n = 3) were also identified.

Conclusion

We have classified the final 54 diagnoses in 11 distinctive biochemical profiles and described them through 20 clinical features. To identify the specific molecular cause of abnormal NT profiles, (targeted) genomics might be used, to improve diagnosis and allow early treatment of complex and rare neurological genetic diseases.