Nanomedicines for chronic non-infectious arthritis: the clinician's perspective

Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent chronic health conditions. However, despite recent advances in medical therapeutics, their treatment still represents an unmet medical need because of safety and efficacy concerns with currently prescribed drugs. Accordingly, there is an urgent need to develop and test new drugs for RA and OA that selectively target inflamed joints thereby mitigating damage to healthy tissues.Conceivably, biocompatible, biodegradable, disease-modifying antirheumatic nanomedicines (DMARNs) could represent a promising therapeutic approach for RA and OA. To this end, the unique physicochemical properties of drug-loaded nanocarriers coupled with pathophysiological characteristics of inflamed joints amplify bioavailability and bioactivity of DMARNs and promote their selective targeting to inflamed joints. This, in turn, minimizes the amount of drug required to control articular inflammation and circumvents collateral damage to healthy tissues. Thus, nanomedicine could provide selective control both in space and time of the inflammatory process in affected joints.However, bringing safe and efficacious DMARNs for RA and OA to the marketplace is challenging because regulatory agencies have no official definition of nanotechnology, and rules and definitions for nanomedicines are still being developed. Although existing toxicology tests may be adequate for most DMARNs, as new toxicity risks and adverse health effects derived from novel nanomaterials with intended use in humans are identified, additional toxicology tests would be required. Hence, we propose that detailed pre-clinical in vivo safety assessment of promising DMARNs leads for RA and OA, including risks to the general population, must be conducted before clinical trials begin.     

Analysis of polymorphisms and haplotypes in genes associated with vascular tone,hypertension and oxidative stress in Mexican-Mestizo women with severe preeclampsia

ObjectiveSeveral studies have reported the association of genes related to vascular tone, hypertension, oxidative stress and preeclampsia. We investigated the possible association among three polymorphisms in eNOS (as well their haplotypes): one of MTHFR, one of GSTP1 and one of AGT, with severe preeclampsia in Mexican-Mestizo women.MethodsTwo hundred thirty women with severe preeclampsia and 350 control subjects were genotyped; for rs2070744 and rs1799983 of eNOS, rs1801133 of MTHFR, rs1695 of GSTP1 and rs699 of AGT we used real-time PCR allelic discrimination and for VNTR of eNOS, PCR. Allele frequency differences were assessed by χ². Logistic regression was used to test for associations and for haplotype frequencies using Haploview 4.2.ResultsGenotypic and allelic distribution of the polymorphisms was similar between cases and controls; likewise, haplotype frequencies of the three polymorphisms of eNOS did not differ significantly.ConclusionsTo our knowledge, this is the first time that these polymorphisms have been analyzed together and exclusively in women with severe preeclampsia. However, we did not find an association between polymorphisms of eNOS, MTHFR, GSTP1 and AGT with severe preeclampsia in our population. Additionally, we observed differences in the distribution of the alleles and genotypes of these polymorphisms in our population in comparison to those described in other ethnic groups.     

Prognosis of patients with adenocarcinoma of the lung and mediastinal lymph node metastases undergoing pulmonary resection

Of 57 patients who were operated on for adenocarcinoma of the lung during the period 1966-1970, 18 with mediastinal lymph node metastases successfully underwent potentially curative pulmonary resection combined with complete mediastinal lymph node dissection. The 5-year survival rate was nil. In light of this poor outlook, we do not recommend surgery as the primary treatment of choice in patients with adenocarcinoma of the lung and known mediastinal lymph node metastases.     

Morbidity and mortality after peritoneovenous shunt surgery for refractory ascites.

A prospective analysis of the morbidity and mortality after peritoneovenous shunting was carried out in 25 patients who had a total of 27 shunts for refractory ascites. Major complications were limited to the patients in whom ascites was secondary to hepatic rather than peritoneal disease. Immediate postoperative complications followed 17 out of the 23 shunts carried out in patients with liver disease and included septicaemia (two), profound hypotension (two), pulmonary oedema (one), and clinically evident disseminated intravascular coagulation (14). Long term morbidity was again limited to the patients with liver disease and included chronic shunt infection (two) and major venous thrombosis (two). Shunt associated mortality was only seen in the patients with liver disease. Despite late shunt blockage in five long term survivors with alcoholic liver disease fluid retention was easily controlled by simple medical means probably because of improved liver function associated with abstinence from alcohol. It is concluded that: (1) patients with hepatic and malignant ascites respond differently to the insertion of a peritoneovenous shunt; (2) Shunt patency should be monitored regularly in patients with liver disease and, because of the potential for septic and thrombotic complications, if blocked the shunt should be removed and; (3) because of the morbidity and mortality of peritoneovenous shunt surgery in patients with liver disease and refractory ascites, an alternative mode of therapy, such as repeated ultrafiltration and reinfusion of ascitic fluid, may be a more effective initial therapeutic approach especially in patients in whom there is a reversible element to their underlying liver disease.     

Use of somatostatin analogue scintigraphy in the localization of recurrent medullary thyroid carcinoma

Detection of recurrence of medullary thyroid carcinoma (MTC) remains a diagnostic problem. Increased serum tumour marker levels frequently indicate recurrence while conventional imaging techniques (CIT) are non-diagnostic. In this study, we performed indium-111 octreotide scintigraphy and CIT in a series of 20 patients with MTC presenting with elevated serum tumour markers after surgery. ¹¹¹In-octreotide whole-body studies detected 15 pathological uptake foci in 11 of the 20 patients studied and CIT detected 17 lesions in 11 of the 20 patients. Ten patients underwent reoperation, five of them with positive ¹¹¹In-octreotide scintigraphy and CIT and two with positive isotopic exploration and negative CIT. Surgical findings demonstrated that the results of isotopic study and CIT had been false-positive for MTC in one case (sarcoidosis). The six patients with true-positive ¹¹¹In-octreotide studies had significantly higher basal calcitonin (CT) and carcinoembryonic antigen (CEA) levels than the patients with negative isotopic studies. The expression of somatostatin receptor (SSTR) subtypes by PC-PCR could be investigated in four cases with a positive isotopic study. Among the three cases with a true-positive study, SSTR2, the SSTR subtype that preferentially binds to the somatostatin analogue octreotide, was detected in two, SSTR5 was demonstrated in the three, and SSTR3 was detected in one. No subtype of SSTR was detected in the case with a final diagnosis of sarcoidosis. We conclude that ¹¹¹In-octreotide has limited sensitivity in detecting recurrence in patients with MTC, although its sensitivity may improve with high serum CT levels. This radionuclide imaging technique should be employed when conventional imaging techniques are negative or inconclusive or when the presence of somatostatin receptors may provide the basis for treatment with somatostatin analogues. Received 5 April and in revised form 27 July 1998     

Hemophilic arthropathy

The most common clinical manifestation of hemophilia is arthropathy secondary to recurrent hemarthroses and chronic synovitis. Joint-surface erosions secondary to chronic synovitis often occur in early childhood and progress to advanced arthropathy by late adolescence. The knee, elbow, ankle, hip, and shoulder are the most commonly involved joints. Management of hemophilic arthropathy has advanced with the development of purified clotting factor concentrates and procedures to prevent chronic synovitis. Radiosynovectomy using beta particle-emitting radiocolloids has been effective in dramatically reducing the frequency of hemarthroses and resolving chronic synovitis. The most common surgical procedures used to manage hemophilic arthropathy are synovectomy, joint debridement, fusion, and joint arthroplasty. Late infection and arthrofibrosis complicate joint arthroplasty more often in these patients than in patients with other forms of arthritis. The high incidence of late infection may relate to frequent intravenous self-infusion of clotting factor combined with immune suppression. Despite the medical and surgical complexities of hemophilic arthropathy, orthopaedic procedures have a high incidence of patient satisfaction.