Is rotation the mode of failure in pertrochanteric fractures fixed with nails? Theoretical approach and illustrative cases

European Journal of Orthopaedic Surgery & Traumatology - The present article reviews data from biomechanical and clinical studies which indicate that rotational instability can cause failure of...     

A novel unstable mutation in mitochondrial DNA responsible for maternally inherited diabetes and deafness

OBJECTIVE

The m.3243A>G mutation in mitochondrial DNA (mtDNA) is responsible for maternally inherited diabetes and deafness (MIDD). Other mtDNA mutations are extremely rare.

RESEARCH DESIGN AND METHODS

We studied a patient presenting with diabetes and deafness who does not carry the m.3243A>G mutation.

RESULTS

We identified a deficiency of respiratory chain complex I in the patient’s fibroblasts. mtDNA sequencing revealed a novel mutation that corresponds to an insertion of one or two cytosine residues in the coding region of the MT-ND6 gene (m.14535_14536insC or CC), leading to premature stop codons. This heteroplasmic mutation is unstable in the patient’s somatic tissues.

CONCLUSIONS

We describe for the first time an unstable mutation in a mitochondrial gene coding for a complex I subunit, which is responsible for the MIDD phenotype. This mutation is likely favored by the m.14530T>C polymorphism, which is homoplasmic and leads to the formation of an 8-bp polyC tract responsible for genetic instability.The most common form of maternally inherited diabetes and deafness (MIDD) is associated with the m.3243A>G mutation in mitochondrial DNA (mtDNA), which is located in the tRNA^Leu gene (1). The mutation that affects up to 1% of diabetic patients leads to both impaired glucose-induced insulin secretion (2) and progressive β-cell loss (3). However, in some rare cases characterized by a highly suggestive phenotype but without m.3243A>G mutation, geneticists should look for other diabetes-prone variants (4). Here, we describe a patient presenting an MIDD phenotype who carries a novel unstable mutation in the mitochondrial MT-ND6 gene responsible for a deficiency in the respiratory chain complex I.     

Interplay between VEGF-A and cMET signaling in human vestibular schwannomas and schwann cells

Vestibular schwannoma (VS), the fourth most common intracranial tumor, arises from the Schwann cells of the vestibular nerve. Although several pathways have been independently implicated in VS pathobiology, interactions among these pathways have not been explored in depth. We have investigated the potential cross-talk between hepatocyte growth factor (HGF) and vascular endothelial growth factor-A (VEGF-A) in human VS, an interaction that has been described in other physiological and pathological cell types. We affirmed previous findings that VEGF-A signaling is aberrantly upregulated in VS, and established that expression of HGF and its receptor cMET is also significantly higher in sporadic VS than in healthy nerves. In primary human VS and Schwann cell cultures, we found that VEGF-A and HGF signaling pathways modulate each other. siRNAs targeting cMET decreased both cMET and VEGF-A protein levels, and siRNAs targeting VEGF-A reduced cMET expression. Additionally, siRNA-mediated knockdown of VEGF-A or cMET and pharmacologic inhibition of cMET decreased cellular proliferation in primary human VS cultures. Our data suggest cross-talk between these 2 prominent pathways in VS and highlight the HGF/cMET pathway as an additional important therapeutic target in VS.     

Effect of Mechanically Treated Recycled Aggregates on the Long Term Mechanical Properties and Durability of Concrete

The objective of this research was to study the effect of an optimal mechanical treatment method to reduce the mortar adhered on recycled aggregates (RCA) on the long-term mechanical properties and durability of concretes containing RCA at different replacement levels. It was found that concretes incorporating treated RCA exhibited sharper and more significant increase on 90- and 365-day compressive strengths than any other investigated mixture. The same mixtures also benefitted from a ‘shrinkage-controlling’ effect, where strains and mass losses were reduced by almost 15% and 10%, respectively, compared to the reference concrete. While sulfate resistance and carbonation resistance are predominantly defined by the hydration products available within the cement paste and not to a large extent by the aggregate type and quality, the incorporation of either treated or untreated RCA in concrete did not appear to expose RACs to significant durability threats.     

Female sexual behavior is disrupted in a preclinical mouse model of PCOS via an attenuated hypothalamic nitric oxide pathway

Women with polycystic ovary syndrome (PCOS) frequently experience decreased sexual arousal, desire, and sexual satisfaction. While the hypothalamus is known to regulate sexual behavior, the specific neuronal pathways affected in patients with PCOS are not known. To dissect the underlying neural circuitry, we capitalized on a robust preclinical animal model that reliably recapitulates all cardinal PCOS features. We discovered that female mice prenatally treated with anti-Müllerian hormone (PAMH) display impaired sexual behavior and sexual partner preference over the reproductive age. Blunted female sexual behavior was associated with increased sexual rejection and independent of sex steroid hormone status. Structurally, sexual dysfunction was associated with a substantial loss of neuronal nitric oxide synthase (nNOS)-expressing neurons in the ventromedial nucleus of the hypothalamus (VMH) and other areas of hypothalamic nuclei involved in social behaviors. Using in vivo chemogenetic manipulation, we show that nNOS^VMH neurons are required for the display of normal sexual behavior in female mice and that pharmacological replenishment of nitric oxide restores normal sexual performance in PAMH mice. Our data provide a framework to investigate facets of hypothalamic nNOS neuron biology with implications for sexual disturbances in PCOS.

Polycystic ovary syndrome (PCOS) is a highly prevalent disease affecting 5 to 18% of women of reproductive age worldwide (1, 2). PCOS is diagnosed upon the presence of at least two out of three prime features: high circulating levels of androgens (hyperandrogenism), menstrual irregularities (oligo-anovulation), and polycystic-like ovarian morphology (2, 3). Beyond its implications leading to female infertility, the disease is associated with several metabolic disruptions, cardiovascular diseases, and psychosocial disorders (4). Among these neurological implications, it has become clear that approximately 30% or more of patients with PCOS experience sexual dysfunctions, with clinical studies reporting a high risk of low sexual arousal, desire, and satisfaction and impaired lubrication and orgasm (5–9). These symptoms allude to disturbances in brain circuits controlling sexual function in the context of PCOS.Neural circuits driving female sexual behaviors are conserved among vertebrate species operating under the influence of sex steroid hormone modulation, which is paramount for partner interaction, receptivity, and sexual performance (10, 11). Indeed, gonadal sex hormones are implicated in shaping circuit architecture in the hypothalamus during development and activating these neonatally programmed circuits over reproductive adult life in many species (12–16). The hypothalamus integrates sensorial stimuli and autonomic arousal from endogenous sex drive cues (e.g., estrous phase, energy status, hormone milieu, genital stimulation) to convey this information to other brain areas and peripheral nerves (10, 17). The ventromedial nucleus of the hypothalamus (VMH) is considered the hub of specialized neurons, with intrinsic properties driving different components of sexual behavior (18–21). The VMH harbors neurons expressing neuronal nitric oxide synthase (nNOS), the enzyme responsible for the production of nitric oxide (NO), a key gaseous neurotransmitter that stimulates female sexual behavior (22, 23) and communicates with other circuits within the social brain (24, 25). Despite current advances unraveling novel pathways in the female sexual brain with specific behavioral responses, there is a clear lack of knowledge on how disturbances in these circuits may participate in sexual dysfunctions affecting one-third of women with PCOS.Growing evidence indicates that androgen excess in utero induces a developmental reprogramming of the female fetal brain toward the manifestation of PCOS traits later in life (26–29). Some studies have suggested that the clinical signs of hyperandrogenism have detrimental sexual effects (5), indicating a negative correlation between androgen levels and sexual function in PCOS. In recent years, it has been proposed that prenatal anti-Müllerian hormone excess may trigger gestational hyperandrogenism via the inhibition of placental aromatase (29, 30) and that women with PCOS display higher circulating levels of androgens and AMH during pregnancy as compared to healthy women (29, 31). Prenatal AMH-treated mice (PAMH) reliably recapitulate all the mouse equivalents of the PCOS Rotterdam criteria (29, 32) and are thus a preclinical model to mimic the human PCOS condition. PAMH female mice also display pronounced neuroendocrine dysfunction leading to exacerbated luteinizing hormone (LH) secretion (29), as in women with PCOS (33), denoting the presence of prenatally reprogrammed defects within the gonadotropin-releasing hormone (GnRH) neuronal network. Thus, prenatal AMH excess–mediated disruptions in the female brain may be key to understanding the pathophysiology of PCOS.Here, we investigated whether prenatal AMH excess could underpin defects in sex circuits promoting sexual dysfunction in PCOS-like female mice. We uncovered a profound decrease of nNOS and progesterone receptor (PR) expression in the VMH. These anatomical changes were also associated with significant impairment of sexual receptivity in PCOS-like female mice. Nevertheless, normal sexual function in PAMH female mice was restored to control levels upon peripheral injection of NO donor. Performing a series of acute functional manipulations in freely moving female mice, we showed that chemogenetic silencing of nNOS^VMH neurons in control female mice recapitulates PCOS-like sexual dysfunctions. Taken together, we unveiled a brain pathway potentially underpinning the etiology of low sexual drive in PCOS while pointing to prospective therapeutic approaches to rescue normal sexual function in these women.     

The neutrophil, not the tumor: serum CA 15-3 elevation as a result of granulocyte--colony-stimulating factor-induced neutrophil MU1C overexpression and neutrophilia in patients with breast carcinoma receiving adjuvant chemotherapy

BACKGROUND: Patients with resected breast carcinoma who received granulocyte-colony-stimulating factor (G-CSF)-supported adjuvant chemotherapy exhibited an increase in their serum CA 15-3 levels. The authors investigated the role of G-CSF-induced neutrophil MUC1 expression in this setting. METHODS: Twenty-two patients with resected early breast carcinoma and 6 patients with high-grade lymphoma received chemotherapy cycles with or without G-CSF support. When given, G-CSF was administered for either 5 or 10 days per cycle. Immunocytochemical staining and flow cytometric analysis of peripheral blood neutrophils and bone marrow myeloid cells for MUC1 epitopes were performed during treatment. RESULTS: At baseline, the median serum CA 15-3 was 16 U/mL, with weak MUC1 expression in peripheral neutrophils (median immunocytochemical score [ICCS] = 40, flow cytometric score [FCS] = 211 antibody molecules per neutrophil). For patients receiving chemotherapy cycles with 5-day G-CSF support, median CA 15-3 levels increased moderately (median = 28 U/mL; P = 0.016) and absolute neutrophil counts (ANC) did not increase, whereas ICC staining showed a moderate increase (median ICCS = 105; P = 0.015). For patients receiving chemotherapy cycles with 10-day G-CSF, serum CA 15-3 levels increased 2-4-fold from baseline levels and reached abnormal levels (median = 47; P < 0.0005) and the ANC increased (median = 21,400/mm(3); P = 0.007), whereas significant induction of MUC1 expression occurred in the cell membrane and mostly in the cytoplasm of neutrophils (median ICCS = 162; P = 0.001). Flow cytometry detected increased cytoplasmic, but not surface, neutrophil MUC1 expression in the 10-day G-CSF group only (baseline median FCS = 3975, 4th cycle median = 6327 molecules per cell; P = 0.028). In the bone marrow, induction of MUC1 expression was observed in the 10-day G-CSF group only in band forms and neutrophils, but not in more immature myeloid cells. Serum CA 15-3 levels and ICC score were found to demonstrate a linear relation. When ICCS and ANC were incorporated in a combined score, its relation with serum CA 15-3 levels demonstrated a parabolic (cubic) pattern. Serum CA 15-3 levels, ANC, and neutrophil MUC1 staining returned to baseline after the completion of therapy. No excess of malignant recurrences were observed. CONCLUSIONS: Women with resected breast carcinoma who received G-CSF-primed chemotherapy showed serum CA 15-3 elevation due to an increase in peripheral blood neutrophil number and induced neutrophil cytoplasmic MUC1 expression, which was caused by G-CSF. Physicians should be aware of this interaction.     

Ki-67 proliferation index: correlation with prognostic parameters and outcome in multiple myeloma

The nuclear protein Ki-67 is a proliferation index, as it is expressed only by dividing cells. In this study, we investigated the clinical significance of Ki-67 determination on bone marrow biopsies of 35 patients with newly diagnosed multiple myeloma (MM). We examined the correlation of Ki-67 with other MM proliferation-related factors: interleukin-6 (IL-6), IL-10, bone marrow infiltration by plasma cells, serum lactate dehydrogenase (LDH), and beta 2 microglobulin (b2M). Ki-67 expression was also correlated with the survival rate of the patients. The results showed that Ki-67 expression increases with increasing stage of disease according to Durie-Salmon (classification stage III vs. I and II, p < 0.001). Furthermore, infiltration, IL-6, LDH, and b2M increase significantly with advancing stage of disease (p < 0.004). All parameters studied were significantly higher in patients versus controls. Ki-67 correlated with IL-6 (r: 0.422, p < 0.01), LDH (r: 0.437, p < 0.01), and b2M (r: 0.478, p < 0.004). There was a marked difference in survival between patients with MM with Ki-67 greater than 8% and patients with Ki-67 less than 8%, in favor of the latter (p < 0.07). We conclude that Ki-67 determination during routine pathological analysis of bone marrow in newly diagnosed MM could provide useful information about the proliferative activity and prognosis of the disease.     

Validity of SF-12 summary scores in a Greek general population

Background  

The 12-item Health Survey (SF-12) was developed as a shorter alternative to the SF-36 for use in large-scale studies, particularly when overall physical and mental health are the outcomes of interest instead of the typical eight-scale profile. The main purpose of this study was to assess the validity of the Greek version of the SF-12.