Heritability of corneal curvature and astigmatism: a videokeratographic child-parent comparison study

PURPOSE: To study child-parent similarities and the heritability of corneal shape by applying a variance component model to videokeratographic data. METHODS: Sixteen astigmatic (keratometric cylinder >/= 1.0 D) and 18 nonastigmatic (keratometric cylinder < 1.0 D) children, 7-14 years of age (mean age, 9.5 years), were enrolled with their parents. Corneal curvature, corneal astigmatism (axis and magnitude), asphericity, corneal uniformity index, and Rabinowitz McDonnell inferior-superior dioptric asymmetry value (I-S value), as well as spherical and astigmatic topographic patterns, were determined by a corneal topographer. Child-parent comparisons were assessed through a 1-way analysis of variance and the chi test. For corneal curvature, corneal astigmatism, and asphericity, heritability was estimated by a variance component model after adjustments were made for age and sex. RESULTS: Both astigmatic and nonastigmatic children showed steeper keratometric values than their parents (P < 0.05). The axis values of corneal astigmatism showed no statistically significant difference (P = 0.684) between astigmatic offspring and their parents, whereas the magnitude values were significantly higher (P < 0.001) in astigmatic children. Altogether, 68% (95% confidence interval [CI], 66%-72%) of child-parent comparisons showed the same topographic pattern between parents and their offspring. Heritability values (48%; 95% CI, 36%-57%) were statistically significant for corneal curvature (P < 0.00001) and <30% for corneal astigmatism and asphericity. CONCLUSIONS: The application of a variance component model to videokeratographic child-parent comparisons suggests that the genetic contribution to corneal shape affects corneal curvature rather than corneal astigmatism.     

In Vitro and In Vivo Antimicrobial Activities of Gallium Nitrate against Multidrug-Resistant Acinetobacter baumannii

Multidrug-resistant Acinetobacter baumannii poses a tremendous challenge to traditional antibiotic therapy. Due to the crucial role of iron in bacterial physiology and pathogenicity, we investigated iron metabolism as a possible target for anti-A. baumannii chemotherapy using gallium as an iron mimetic. Due to chemical similarity, gallium competes with iron for binding to several redox enzymes, thereby interfering with a number of essential biological reactions. We found that Ga(NO₃)₃, the active component of an FDA-approved drug (Ganite), inhibits the growth of a collection of 58 A. baumannii strains in both chemically defined medium and human serum, at concentrations ranging from 2 to 80 μM and from 4 to 64 μM, respectively. Ga(NO₃)₃ delayed the entry of A. baumannii into the exponential phase and drastically reduced bacterial growth rates. Ga(NO₃)₃ activity was strongly dependent on iron availability in the culture medium, though the mechanism of growth inhibition was independent of dysregulation of gene expression controlled by the ferric uptake regulator Fur. Ga(NO₃)₃ also protected Galleria mellonella larvae from lethal A. baumannii infection, with survival rates of ≥75%. At therapeutic concentrations for humans (28 μM plasma levels), Ga(NO₃)₃ inhibited the growth in human serum of 76% of the multidrug-resistant A. baumannii isolates tested by ≥90%, raising expectations on the therapeutic potential of gallium for the treatment of A. baumannii bloodstream infections. Ga(NO₃)₃ also showed strong synergism with colistin, suggesting that a colistin-gallium combination holds promise as a last-resort therapy for infections caused by pan-resistant A. baumannii.     

A tolerability and pharmacokinetic study of a new injectable formulation of disodium clodronate in healthy female volunteers.

Disodium clodronate (dichloromethylene bisphosphonic acid, disodium salt; CAS 22560-50-5) is a bisphosphonate that has demonstrated efficacy in patients with a variety of diseases of enhanced bone resorption. Intramuscular clodronate can determine pain at the injection site, it is therefore particularly useful to co-administer a local anaesthetic with clodronate to reduce pain at the injection site. The tolerability and pharmacokinetic of a new formulation of 100 mg disodium clodronate containing 1% lidocaine (test formulation, Chiesi Farmaceutici S.p.A) were investigated in comparison to the same formulation without the local anaesthetic (Clody) and a marketed formulation containing 1% benzyl alcohol (Clasteon). Thirty healthy female volunteers were treated according to a single dose, double-blind, randomised, three-way cross-over design. The local tolerability was investigated by assessing reddening and hardening at the injection site, and plasma CPK levels. Pain intensity was investigated on the VAS (visual analogue scale) and on the VRS (verbal rating score). Urinary clodronic acid concentrations were determined using a validated specific GC/MS/NCI assay. The statistical analysis on pain assessment showed a significant reduction of pain intensity immediately and up to 2 hours after administration of the new formulation compared to the marketed ones. CPK levels and occurrence of hardening at the injection site did not show statistically significant differences between formulations. No local redness was reported. Clodronate urinary excretion during the 48 h collection interval was not statistically different among the formulations and the 95% confidence intervals were inside the bioequivalence acceptance region, demonstrating comparable bioavailability. It was concluded that the investigated new formulation of 100 mg disodium clodronate was better tolerated than the reference marketed formulations.     

Central nervous system trans-synaptic effects of acute axonal injury: a 1h magnetic resonance spectroscopy study

N-acetylaspartate (NAA) has previously been proposed as a neuronal marker. ¹H magnetic resonance spectroscopy (MRS) is able to detect NAA in brain, and decreases of NAA have been documented after brain injury. The reason for this decrease is not fully understood and neuron loss damage and “dysfunction” have all been proposed. It is hypothesized that acute central nervous system (CNS) deafferentation causes a trans-synaptic NAA decrease and that high resolution ¹H MRS is able to detect such a decrease. To test this hypothesis, an experimental model was used in which axonal lesions were obtained by stretch injury in guinea pig right optic nerve (95–99% crossed fibers). The trans-synaptic concentration of NAA, total creatine (Cr), and the NAA/Cr ratio in lateral geniculate bodies (LGB) and superior colliculi (SC) sample extracts were measured 72 h later by high resolution ¹H MRS. In the left LGB/SC, which is where right optic nerve fibers project, reductions of NAA and NAA/Cr were found whereas Cr levels were normal. NAA, NAA/Cr, and Cr values were all normal in the right LGB/SC. Histology and EM findings revealed no abnormalities. At 7 days, left LGB/SC NAA and NAA/Cr values were in the normal range. It was concluded that 1) acute deafferentation in the CNS causes a trans-synaptic decrease of NAA levels that can be detected by ¹H MRS and 2) NAA decrease may be due to changes of NAA metabolism caused by functional neuronal inactivity rather than neuronal loss, injury or “dysfunction.” ¹H MRS is a potential tool for the study of functional effect of CNS lesions in vivo.     

Placental Antioxidant Defenses and Autophagy-Related Genes in Maternal Obesity and Gestational Diabetes Mellitus

Maternal obesity and gestational diabetes mellitus (GDM) are increasing worldwide, representing risk factors for both mother and child short/long-term outcomes. Oxidative stress, lipotoxicity and altered autophagy have already been reported in obesity, but few studies have focused on obese pregnant women with GDM. Antioxidant and macro/chaperone-mediated autophagy (CMA)-related gene expressions were evaluated herein in obese and GDM placentas. A total of 47 women with singleton pregnancies delivered by elective cesarean section were enrolled: 16 normal weight (NW), 18 obese with no comorbidities (OB GDM(–)), 13 obese with GDM (OB GDM(+)). Placental gene expression was assessed by real-time PCR. Antioxidant gene expression (CAT, GPX1, GSS) decreased, the pro-autophagic ULK1 gene increased and the chaperone-mediated autophagy regulator PHLPP1 decreased in OB GDM(–) vs. NW. On the other hand, PHLPP1 expression increased in OB GDM(+) vs. OB GDM(–). When analyzing results in relation to fetal sex, we found sexual dimorphism for both antioxidant and CMA-related gene expressions. These preliminary results can pave the way for further analyses aimed at elucidating the placental autophagy role in metabolic pregnancy disorders and its potential targetability for the treatment of diabetes outcomes.     

Long-Acting Injectable Antipsychotics in Schizophrenia: Literature Review and Practical Perspective,with a Focus on Aripiprazole Once-Monthly

Introduction

Prevention of relapse is a major challenge in schizophrenia, a disease characterized by poor adherence to antipsychotic medication leading to multiple rehospitalizations and a substantial burden-of-care.

Methods

We narratively review published clinical data from the development of long-acting injectable (LAI) formulations of antipsychotic drugs and examine the comparative effectiveness of oral versus LAIs in schizophrenia, with a focus on the second-generation LAI antipsychotic aripiprazole. Evidence is presented from studies with naturalistic/pragmatic as well as explanatory trial designs, supported by the clinical experience of the authors.

Results

LAI formulations of antipsychotic drugs offer advantages over oral medications and there is good evidence for their use as a first-choice treatment and in younger patients. Key phase III studies have shown aripiprazole once-monthly 400 mg (AOM 400) to be effective and well tolerated, with high rates of adherence and low rates of impending relapse. In a recent randomized trial with a “naturalistic” study design more representative of routine clinical practice, AOM 400 was well tolerated and had significantly greater effectiveness than paliperidone LAI overall and in younger patients aged ≤35 years.

Conclusion

Results across the “full spectrum” of efficacy in traditional clinical trials as well as those encompassing the concept of effectiveness in a more naturalistic setting of real-life clinical practice support the use of AOM 400 as a valid long-term treatment option in schizophrenia overall, as well as earlier in the treatment course, and not solely in situations of poor adherence or when oral antipsychotics have failed.