Osteogenesis imperfecta (OI) is the most common bone genetic disorder and it is characterized by bone brittleness and various degrees of growth disorder. Clinical severity varies widely; nowadays ...eight types are distinguished and two new forms have been recently described although not yet classified. The approach to such a variable and heterogeneous disease should be global and therefore multidisciplinary. For simplicity, the objectives of treatment can be reduced to three typical situations: the lethal perinatal form (type II), in which the problem is survival at birth; the severe and moderate forms (types III-IX), in which the objective is 'autonomy'; and the mild form (type I), in which the aim is to reach 'normal life'. Three types of treatment are available: non-surgical management (physical therapy, rehabilitation, bracing and splinting), surgical management (intramedullary rod positioning, spinal and basilar impression surgery) and medical-pharmacological management (drugs to increase the strength of bone and decrease the number of fractures as bisphosphonates or growth hormone, depending on the type of OI). Suggestions and guidelines for a therapeutic approach are indicated and updated with the most recent findings in OI diagnosis and treatment.
Human skeletal muscle atrophy and a disproportionate force loss occur within a few days of unloading in space and on Earth, but the underlying mechanisms are not fully understood. Disruption of ...neuromuscular junction homeostasis has been proposed as one of the possible causes. Here, we investigated the potential mechanisms involved in this neuromuscular disruption induced by a 10-day unilateral lower limb suspension (ULLS) in humans. Specifically, we investigated hemichannels' upregulation, neuromuscular junction and axonal damage, neurotrophins' receptor downregulation and inflammatory transcriptional signatures. Biomarkers were evaluated at local and systemic levels. At the sarcolemmal level, changes were found to be associated with an increased expression of connexin 43 and pannexin-1. Upregulation of the inflammatory transcripts revealed by deep transcriptomics was found after 10 days of ULLS. The destabilisation of the neuromuscular junction was not accompanied by changes in the secretion of the brain-derived neurotrophic factor and neurotrophin-4, while their receptor, BDNF/NT growth factors receptor (TrkB), decreased. Furthermore, at 5 days of ULLS, there was already a significant upregulation of the serum neurofilament light chain concentration, an established clinical biomarker of axonal injury. At 10 days of ULLS, other biomarkers of early denervation processes appeared. Hence, short periods of muscle unloading induce sarcolemmal hemichannels upregulation, inflammatory transcripts upregulation, neuromuscular junction instability and axonal damage.
To analyze the clinical evidence on the efficacy of phytotherapy in the treatment of calculi in the urinary tract.
To be eligible, full-length articles should include the results of randomized ...controlled trials enrolling patients affected by urolithiasis, reporting any comparison between an experimental herbal agent versus placebo or any active comparator, aimed at preventing the formation or facilitating the dissolution of calculi in any portion of the urinary tract. Fifteen databases were searched for relevant references. The primary outcomes investigated were (i) the reduction of stone size and/or number and (ii) the urinary excretion rates of calcium, urate, or oxalate. The secondary outcome of the review was the adverse effects (AE) of treatment. Risk of bias (ROB) and quality of the evidence were assessed according to Cochrane and GRADE guidelines. We performed a random-effect meta-analysis.
541 articles were retrieved and 16 studies were finally confirmed as eligible. Multiple Cochrane ROB tool items were rated as having high risk of bias in each analyzed trial report. Pooled analysis of continuous data could be performed for three different comparisons: (i) phytotherapy versus citrate as single agent (ii) phytotherapy versus placebo, (iii) preparation of Didymocarpus pedicellata (DP)--combined with other herbal agents--versus placebo. Results showed that citrate is superior to phytotherapy in significantly decreasing both the size of urinary stones (mean difference: phytotherapy, 0.42 mm higher; 95% CI: 0.23 to 0.6; Z = 4.42, P < 0.0001; I2 = 30%) and the urinary excretion rate of urate (mean difference: 42.32 mg/24h higher, 95% CI: 19.44 to 65.19; Z = 3.63, P = 0.0003; I2 = 96%), assessed after 3 months on-therapy. No significant differences in the excretion rates of urinary calcium or oxalate were found. The DP preparation was superior to placebo in inducing total clearance (risk ratio: 6.19, 95% CI: 2.60 to 14.74; Z = 4.12, P < 0.0001; I2 = 0%) and size reduction (mean difference: DP preparation, 4.93 mm lower; 95% CI: -9.18 to -0.67; Z = 2.27, P = 0.02; I2 = 99%) of renal and ureteral stones after 3 months of therapy. No significant differences in the inter-arm variation of excretion rates of urinary calcium or urate were found as result of the pooled phytotherapy-placebo comparison. Herbal remedies were in general devoid of side effects and in few cases citrate appeared to induce GI disturbances in a higher fraction of patients. Most reports did not provide inferential data concerning AE, and meta-analysis was not feasible.
Citrate is more effective than phytotherapy in decreasing the size of existing calculi in the urinary tract and in decreasing the urinary excretion rate of uric acid. A preparation containing Didymocarpus pedicellata combined with other herbal agents induces stone size reduction and clearance significantly better than placebo. Mayor limitations in the applicability of these results are the low quality of the evidence and the multiple sources of bias assessed in the studies included in the present review.
ABSTRACT
The clinical use of anticancer anthra‐cyclines is limited by the development of a distinctive and life‐threatening form of cardiomyopathy upon chronic treatment. Commonly accepted ...mechanistic hypotheses have assigned a pivotal role to iron, which would act as a catalyst for free radical reactions and oxidative stress. Although perhaps involved in acute aspects of anthracycline cardiotoxicity, the role of free radical‐based mechanisms in long‐term effects has been challenged on both experimental and clinical grounds, and alternative hypotheses independent of iron and free radicals have flourished. More recently, studies of the role of C‐13 hydroxy metabolites of anthracyclines have provided new perspectives on the role of iron in the cardio‐toxicity of these drugs, showing that such metabolites can impair intracellular iron handling and homeostasis. The present review applies a multisided approach to the critical evaluation of various hypotheses proposed over the last decade for the role of iron in anthracycline‐induced cardiotoxicity. The main goal of the authors is to build a unifying pattern that would both account for hitherto unexplained experimental observations and help design novel and more rational strategies toward a much‐needed improvement in the therapeutic index of anthracyclines.—Minotti, G., Cairo, G., Monti, E. Role of iron in anthracycline cardiotoxicity: new tunes for an old song? FASEB J. 13, 199–212 (1999)
A series of tetraaryl porphyrins and chlorins were synthesized and tested for photodynamic activity in human colon adenocarcinoma cells.
Photodynamic therapy (PDT) is a cancer treatment involving ...systemic administration of a tumor-localizing photosensitizer; this, when activated by the appropriate wavelength of light, interacts with molecular oxygen to form a toxic, short-lived species known as singlet oxygen, which is thought to mediate cellular death. Photofrin®, a complex mixture of porphyrin oligomers has recently received FDA approval for the photodynamic treatment of esophageal and endobronchial carcinoma, but its photodynamic and toxicity profiles are far from ideal. In the present study we evaluated a series of porphyrin-based PSs, some of which newly synthesized by our group, with the aim to identify agents with more favorable characteristics. For the most effective compounds in the porphyrin series, chlorin analogs were also synthesized; for comparison, the screening also included Photofrin®. Cytotoxicity studies were performed by the MTT assay on a cultured human colon adenocarcinoma cell line (HCT116); the results indicate that the 3,4,5-trimethoxyphenyl, 3OH- and 4OH-phenyl, and the sulfonamidophenyl derivatives are significantly more potent than Photofrin®. Flow cytometric studies and fluorescence microscopy indicate that in PDT-treated HCT116 cells death occurs mainly by apoptosis.
In summary, novel PSs described in the present study, belonging both to the porphyrin and chlorin series, have proven more effective than Photofrin® in killing colon cancer cells in vitro; extending these observation to in vivo models, particularly regarding the deeper reaching chlorin derivatives, might lead to significant advances in the development of tumor PDT.
A panel of eight Zn-phthalocyanines (
1)–(
8), differently substituted on the benzo units, was synthesized either by direct cyclic-tetramerization of substituted phthalonitriles, or by chemical ...transformations of available Zn-phthalocyanines. The phototoxicity of compounds
1–
8 was evaluated in vitro on tumor cells, and their effect compared with those induced by porfimer sodium.
A panel of eight Zn-phthalocyanines (Zn-Pcs) (
1)–(
8), differently substituted on the benzo units, was synthesized either by direct cyclic-tetramerization of substituted phthalonitriles (compounds
1 and
2), or leading from the easily available tetrasulphonyl phthalocyanine to yield the sulfonamido derivatives
3 and
4, or else via the chloromethylation of precedent Zn-Pc followed by reaction with nucleophiles affording the dicationic Zn-Pcs (
5) and (
6) or the neutral Zn-Pcs (
7) and (
8). The phototoxicity of these new compounds was evaluated in vitro on human colon adenocarcinoma cell line (HCT116), and their effect compared with those induced by porfimer sodium. The results are reported as IC
50 values, following exposure of the cells to different Zn-Pcs concentration and irradiation with a 500
W tungsten/halogen white lamp. The cationic Zn-Pc (
5) and (
6) together with the Zn-Pc (
7), featuring 12 methoxy groups, were found good or fairly good photosensitizers while the more lipophilic Zn-Pcs (
1)–(
4) and (
8) were found devoid of activity.
Abstract Tumour hypoxia represents a major obstacle to the success of radiotherapy and chemotherapy. The discovery that the hypoxia-inducible factor 1 (HIF-1) is a master regulator of cellular ...response to low oxygen led to the concept that inhibiting HIF-1 activity may sensitise hypoxic cancer cells to radiation and cytotoxic drugs. In the present study we investigate the effects of HIF-1 modulation on the response of the human colon adenocarcinoma cell line HCT116 to 5-fluorouracil (5FU). Increasing HIF-1 activity, either by exposing cells to hypoxia or by forced expression of a degradation-resistant form of HIF-1α, results in poor cell response to 5FU; conversely, knockdown of HIF-1α by RNA interference prevents hypoxia-induced resistance to 5FU. PMX290, a thioredoxin-1 inhibitor, significantly inhibits HIF-1 activity and concomitantly sensitises hypoxic cells to 5FU. These results were confirmed in HCT116 cells grown as three-dimensional spheroids, a model that more closely reproduces the hypoxic environment of solid tumours.
The synthesis of a panel of seven nonsymmetric 5,10,15,20-tetraarylporphyrins, 13 symmetric and nonsymmetric 5,15-diarylporphyrins, and one 5,15-diarylchlorin is described. In vitro photodynamic ...activities on HCT116 human colon adenocarcinoma cells were evaluated by standard cytotoxicity assays. A predictive quantitative structure−activity relationship (QSAR) regression model, based on theoretical holistic molecular descriptors, of a series of 34 tetrapyrrolic photosensitizers (PSs), including the 24 compounds synthesized in this work, was developed to describe the relationship between structural features and photodynamic activity. The present study demonstrates that structural features significantly influence the photodynamic activity of tetrapyrrolic derivatives: diaryl compounds were more active with respect to the tetraarylporphyrins, and among the diaryl derivatives, hydroxy-substituted compounds were more effective than the corresponding methoxy-substituted ones. Furthermore, three monoarylporphyrins, isolated as byproducts during diarylporphyrin synthesis, were considered for both photodynamic and QSAR studies; surprisingly they were found to be particularly active photosensitizers.
The vas deferens and spermatic vessels entering the inguinal canal through the internal inguinal ring is thought to exclude an intra-abdominal testis. We present a case of high bilateral ...intra-abdominal testes on a 46,XY boy despite the vas deferens and good-sized vessels passing through the deep rings. Data were collected from clinical records, radiology (ultrasound, magnetic resonance imaging MRI), and endocrine blood tests. This case underlines the importance of following the pathway of embryological descent of the testis cranially as well as caudally during diagnostic laparoscopy, to avoid missing this rare anatomical variant.
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