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At least 991 records · Page 55Linked to original sources
PubMed2003

The tragedy of schizophrenia without psychotherapy.

No one who read Frieda Fromm-Reichmann's "Transference Problems in Schizophrenia" could reasonably think about persons with schizophrenia in the same way as before. Her writings made clear that schizophrenia is a human experience with meaning, meaning that is hard to uncover, but it only takes patience, kindness, a tolerance for not understanding as well as for the patient's desperate defenses, and a willingness to understand the human condition at its most painful and to take psychoanalytic ideas seriously when patients talk about them. Understanding persons with schizophrenia means facing facts about ourselves, our families, and our society that we do not want to know, or to know again (in the case of repressed feelings and experiences). Families and professionals are settling for treatments that aim at making the patient a lifelong cripple who is not too disturbing. Psychoeducational programs, which potentially could be helpful, usually give false information which makes worse the burdens of both patients and their families. The ultimate genetic experiment, the Nazi sterilization and annihilation of patients, led to no decrease in schizophrenia in the next generation. Long-term follow-up studies show one third of schizophrenics fully recover within 25 years and another third have social recoveries with or without treatment--and psychological treatments before the neuroleptic era, from "moral treatment" to psychoanalytic therapies, produced superior results, but we are not using them. The central role of terror in producing symptoms and the genesis and psychotherapeutic handling of symptoms, including delusions and hallucinations, will be described.

Affect↗
PubMed2004

Verbal memory deficit in patients with schizophrenia: an important future target for treatment.

Despite more than two-thirds of patients with schizophrenia showing reductions in delusions and hallucinations following optimum available treatment, many are left with crippling cognitive impairments. Neurocognitive deficit is a core feature of schizophrenia, but the question arises as to whether efforts should be geared towards ameliorating and normalizing these deficits. Verbal memory dysfunction is one of the most consistently reported cognitive deficits and among the best predictors of functional outcome in schizophrenia. Therefore, a better understanding of the nature of this deficit could lead to treatments that not only improve the specific systems mediating the impairment, but could also have wider implications for clinical and social outcome.

Antipsychotic Agents↗
PubMed2005

Central venous access devices in patients with hemophilia.

Hemophilia is a hereditary disorder in which the major clinical manifestation is bleeding into the joints, muscles, internal organs and the CNS, often without any obvious trauma. Bleeding can be fatal as in the case of CNS hemorrhage, or severely debilitating following repeated bleeding into joints that results in crippling arthritis. Treatment for hemophilia includes the intravenous administration of clotting factor concentrates to replace the missing or defective protein. Venous access is therefore critical to the treatment of hemophilia and the prevention of complications due to bleeding. According to the US Centers for Disease Control and Prevention, approximately half of patients less than 16 years of age and one-third of all patients with hemophilia receive regular prophylactic injections of clotting factor concentrates. Prophylaxis, or the regular scheduled administration of antihemophilic factor concentrate, is effective in preventing bleeding. Among those patients with severe disease, in the absence of prophylaxis, approximately 13 bleeds, including nine joint hemorrhages, occur annually. In contrast, when prophylaxis is administered, the annual number of total and joint bleeds decreases to five and three, respectively. One of the major barriers to the more wide-spread use of prophylaxis is venous access. While peripheral venipuncture remains the first choice for venous access, central venous access devices are frequently used to facilitate repeated and/or urgent administration of clotting factor concentrates. The advantages of central venous access devices are well recognized in certain treatment regimens such as prophylaxis and immune tolerance therapy, as well as certain patient groups such as young children in whom venipuncture is often difficult and traumatic, and adults with scarred veins. Central venous access devices also allow earlier commencement of both home treatment and prophylaxis. The goal of this review is to discuss the different types of central venous access devices and their role in the management of hemophilia to provide practitioners that care for patients with hemophilia with the necessary information to make sound therapeutic recommendations to their patients.

Blood Vessel Prosthesis↗
PubMedDate not supplied

Overexposure of radiation therapy patients in Panama: problem recognition and follow-up measures.

This report summarizes and analyzes the responses of various organizations that provided assistance to the National Oncology Institute (Instituto Oncológico Nacional, ION) of Panama following the overexposure of 28 radiation therapy patients at the ION in late 2000 and early 2001. The report also looks at the long-term measures that were adopted at the ION in response to the overexposure incident, as well as implications that the incident has for other cancer treatment centers worldwide. In March 2001, the director of the ION was notified of serious overreactions in patients undergoing radiation therapy for cancer treatment. Of the 478 patients treated for pelvic cancers between August 2000 and March 2001, 3 of them had died, possibly from an overdose of radiation. In response, the Government of Panama invited international experts to carry out a full investigation of the situation. Medical physicists from the Pan American Health Organization (PAHO) were among those invited. They ascertained that 56 patients treated with partially blocked teletherapy fields for cancers of the uterine cervix, endometrium, prostate, or rectum, had had their treatment times calculated using a computerized treatment planning system. PAHO's medical physicists calculated the absorbed doses received by the patients and found that, of these 56 patients, only 11 had been treated with acceptable errors of +/-5%. The doses received by 28 of the 56 patients had errors ranging from +10 to +105%. These are the patients identified by ION physicists as overexposed. Twenty-three of the 28 overexposed patients had died by September 2005, with at least 18 of the deaths being from radiation effects, mostly rectal complications. The clinical, psychological, and legal consequences of the overexposures crippled cancer treatments in Panama and prompted PAHO to assess radiation oncology practices in the countries of Latin American and the Caribbean. ION clinicians evaluated the outcome of 125 non-overexposed patients who had been treated in the same time period and for the same cancer sites as the overexposed patients. The clinicians uncovered a larger recurrence of cervical cancers than expected. The finding prompted PAHO to launch an initiative for the accreditation of radiation oncology centers in Latin America and the Caribbean, working in collaboration with professional societies for radiation oncologists, medical physicists, and radiotherapy technologists. The Latin American Association for Radiation Oncology (Asociación Latinoamericana de Terapia Radiante Oncológica) has established an accreditation commission. Accreditation will require that centers implement a comprehensive radiation oncology quality assurance program that follows international guidelines. Statistical data on patient outcomes will be collected in order to document needs in radiotherapy centers in Latin America and the Caribbean and to define future strategies for cancer treatment.

Humans↗
PubMed2002

Angiotensin II blockade reduces radiation-induced proliferation in experimental radiation nephropathy.

Total-body irradiation or renal irradiation is followed by a well-defined sequence of changes in renal function leading eventually to renal failure. Previous studies in a rat model have shown that inhibition of angiotensin-converting enzyme or blockade of angiotensin II receptors can prevent the structural and functional changes that occur after renal irradiation, and that these interventions are particularly important between 3 and 10 weeks after irradiation. We have now shown that in the same rat model, total-body irradiation induces proliferation of renal tubular cells (i.e., an increase in the number of cells staining positive for proliferating cell nuclear antigen) within 5 weeks after irradiation. Treatment with an angiotensin II receptor blocker delays this radiation-induced tubular proliferation and decreases its magnitude. Renal radiation also induces proliferation of glomerular cells, but the relative increase in glomerular proliferation is not as great as that seen in renal tubular cells, and the increase is not delayed or decreased by treatment with an angiotensin II receptor blocker. We hypothesize that angiotensin II receptor blockers exert their beneficial effect in radiation nephropathy by delaying the proliferation (and hence the eventual mitotic death) of renal tubular cells that have been genetically crippled by radiation.

Angiotensin Receptor Antagonists↗
PubMed2001

The physiological kinetics of nitrogen and the prevention of decompression sickness.

Decompression sickness (DCS) is a potentially crippling disease caused by intracorporeal bubble formation during or after decompression from a compressed gas underwater dive. Bubbles most commonly evolve from dissolved inert gas accumulated during the exposure to increased ambient pressure. Most diving is performed breathing air, and the inert gas of interest is nitrogen. Divers use algorithms based on nitrogen kinetic models to plan the duration and degree of exposure to increased ambient pressure and to control their ascent rate. However, even correct execution of dives planned using such algorithms often results in bubble formation and may result in DCS. This reflects the importance of idiosyncratic host factors that are difficult to model, and deficiencies in current nitrogen kinetic models. Models describing the exchange of nitrogen between tissues and blood may be based on distributed capillary units or lumped compartments, either of which may be perfusion- or diffusion-limited. However, such simplistic models are usually poor predictors of experimental nitrogen kinetics at the organ or tissue level, probably because they fail to account for factors such as heterogeneity in both tissue composition and blood perfusion and non-capillary exchange mechanisms. The modelling of safe decompression procedures is further complicated by incomplete understanding of the processes that determine bubble formation. Moreover, any formation of bubbles during decompression alters subsequent nitrogen kinetics. Although these factors mandate complex resolutions to account for the interaction between dissolved nitrogen kinetics and bubble formation and growth, most decompression schedules are based on relatively simple perfusion-limited lumped compartment models of blood: tissue nitrogen exchange. Not surprisingly, all models inevitably require empirical adjustment based on outcomes in the field. Improvements in the predictive power of decompression calculations are being achieved using probabilistic bubble models, but divers will always be subject to the possibility of developing DCS despite adherence to prescribed limits.

Algorithms↗
PubMed2005

Gout in solid organ transplantation: a challenging clinical problem.

Hyperuricaemia occurs in 5-84% and gout in 1.7-28% of recipients of solid organ transplants. Gout may be severe and crippling, and may hinder the improved quality of life gained through organ transplantation. Risk factors for gout in the general population include hyperuricaemia, obesity, weight gain, hypertension and diuretic use. In transplant recipients, therapy with ciclosporin (cyclosporin) is an additional risk factor. Hyperuricaemia is recognised as an independent risk factor for cardiovascular disease; however, whether anti-hyperuricaemic therapy reduces cardiovascular events remains to be determined. Dietary advice is important in the management of gout and patients should be educated to partake in a low-calorie diet with moderate carbohydrate restriction and increased proportional intake of protein and unsaturated fat. While gout is curable, its pharmacological management in transplant recipients is complicated by the risk of adverse effects and potentially severe interactions between immunosuppressive and hypouricaemic drugs. NSAIDs, colchicine and corticosteroids may be used to treat acute gouty attacks. NSAIDs have effects on renal haemodynamics, and must be used with caution and with close monitoring of renal function. Colchicine myotoxicty is of particular concern in transplant recipients with renal impairment or when used in combination with ciclosporin. Long-term urate-lowering therapy is required to promote dissolution of uric acid crystals, thereby preventing recurrent attacks of gout. Allopurinol should be used with caution because of its interaction with azathioprine, which results in bone marrow suppression. Substitution of mycophenylate mofetil for azathioprine avoids this interaction. Uricosuric agents, such as probenecid, are ineffective in patients with renal impairment. The exception is benzbromarone, which is effective in those with a creatinine clearance >25 mL/min. Benzbromarone is indicated in allopurinol-intolerant patients with renal failure, solid organ transplant or tophaceous/polyarticular gout. Monitoring for hepatotoxicty is essential for patients taking benzbromarone. Physicians should carefully consider therapeutic options for the management of hypertension and hyperlipidaemia, which are common in transplant recipients. While loop and thiazide diuretics increase serum urate, amlodipine and losartan have the same antihypertensive effect with the additional benefit of lowering serum urate. Atorvastatin, but not simvastatin, may lower uric acid, and while fenofibrate may reduce serum urate it has been associated with a decline in renal function. Gout in solid organ transplantation is an increasing and challenging clinical problem; it impacts adversely on patients' quality of life. Recognition and, if possible, alleviation of risk factors, prompt treatment of acute attacks and early introduction of hypouricaemic therapy with careful monitoring are the keys to successful management.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Ricin. Mechanisms of cytotoxicity.

Ricin is a heterodimeric protein produced in the seeds of the castor oil plant (Ricinus communis). It is exquisitely potent to mammalian cells, being able to fatally disrupt protein synthesis by attacking the Achilles heel of the ribosome. For this enzyme to reach its substrate, it must not only negotiate the endomembrane system but it must also cross an internal membrane and avoid complete degradation without compromising its activity in any way. Cell entry by ricin involves a series of steps: (i) binding, via the ricin B chain (RTB), to a range of cell surface glycolipids or glycoproteins having beta-1,4-linked galactose residues; (ii) uptake into the cell by endocytosis; (iii) entry of the toxin into early endosomes; (iv) transfer, by vesicular transport, of ricin from early endosomes to the trans-Golgi network; (v) retrograde vesicular transport through the Golgi complex to reach the endoplasmic reticulum; (vi) reduction of the disulphide bond connecting the ricin A chain (RTA) and the RTB; (vii) partial unfolding of the RTA to render it translocationally-competent to cross the endoplasmic reticulum (ER) membrane via the Sec61p translocon in a manner similar to that followed by misfolded ER proteins that, once recognised, are targeted to the ER-associated protein degradation (ERAD) machinery; (viii) avoiding, at least in part, ubiquitination that would lead to rapid degradation by cytosolic proteasomes immediately after membrane translocation when it is still partially unfolded; (ix) refolding into its protease-resistant, biologically active conformation; and (x) interaction with the ribosome to catalyse the depurination reaction. It is clear that ricin can take advantage of many target cell molecules, pathways and processes. It has been reported that a single molecule of ricin reaching the cytosol can kill that cell as a consequence of protein synthesis inhibition. The ready availability of ricin, coupled to its extreme potency when administered intravenously or if inhaled, has identified this protein toxin as a potential biological warfare agent. Therapeutically, its cytotoxicity has encouraged the use of ricin in 'magic bullets' to specifically target and destroy cancer cells, and the unusual intracellular trafficking properties of ricin potentially permit its development as a vaccine vector. Combining our understanding of the ricin structure with ways to cripple its unwanted properties (its enzymatic activity and promotion of vascular leak whilst retaining protein stability and important immunodominant epitopes), will also be crucial in the development of a long awaited protective vaccine against this toxin.

Animals↗
PubMed2006

Current status of anti-picornavirus therapies.

Picornaviruses are important human pathogens causing severe morbidity and some mortality with the potential to cause worldwide crippling disease. Currently, there are few treatments for many of the viruses in the Picornaviridae, For rhinoviruses, there are no approved treatments, although ruprintrivir looks promising in clinical trials and pyridazinyl oxime ethers may prove useful. Poliovirus treatments are needed to supplement the World Health Organization's polio eradication plan in order to treat infections caused by reversion of the attenuated vaccine virus and to supplement vaccine coverage control in polio endemic areas. However, no promising compounds for treatment of poliovirus have been developed due to the efficacy of the vaccines in use. Broad-spectrum inhibitors developed for other picornavirus may be useful for poliovirus infections. Coxsackievirus infections in children and in infants are being treated with pleconaril with some efficacy in reducing mortality and improving recovery, albeit the treatment is often on a compassionate use basis. There are no therapies for echovirus infections. Very little drug discovery research is being done to develop inhibitors for echovirus infections, probably due to the broad-spectrum inhibition exhibited by capsid binding agents and protease inhibitors discovered for treatment of other picornaviruses. For example, pyridazinyl oxime ethers are inhibitory to most echoviruses. Treatments for enterovirus infections are also limited, although in a small clinical trial, milrinone seemed to reduce mortality and improve recovery from EV71-induced pulmonary edema. Thus, these results strongly emphasize the need for the development of potent and nontoxic compounds for the treatment of picornavirus infections.

Animals↗
PubMed2001

The role of retroviral dUTPases in replication and virulence.

Several retroviruses, including equine infectious anemia virus (EIAV), visna virus, caprine arthritis-encephalitis virus (CAEV) and feline immunodeficiency virus (FIV) encode dUTPase. The role of this enzyme in the replication of these viruses has been scrutinized, with particular emphasis on potential roles for dUTPase in virulence and viral mutation rate. Overall, the results of these studies have indicated a central role for dUTPase in facilitating productive viral replication in non-dividing cells. The requirement for dUTPase in EIAV, which replicates exclusively in macrophages, may be the most stringent. Studies of dUTPase mutants of virulent EIAV clones suggest that the enzyme is a major determinant of virulence. In contrast, FIV readily replicates in dividing cell populations such as CD4+ and CD8+ T cells, and B cells as well as in non-dividing macrophages. Thus, the virus burden and disease sequelae are lowered in cats infected with a dUTPase-minus FIV relative to cats infected with wild type FIV, but not totally abrogated. Growth in macrophages is attenuated with the DU-minus FIV with evidence of a 5 to 8-fold increase in G-->A transition mutations in viral integrants present in macrophages. These findings are consistent with an increase in uracil misincorporation in the absence of dUTPase, resulting in transition mutations that cripple the virus. Effects on virus replication and disease production have also been noted for dUTPase-deleted CEAV and visna virus. While HIV and SIV do not encode dUTPase some reports suggest that other viral and host cell factors may substitute for its activity. Betaretroviruses also encode dUTPase and while several of these cause significant disease, the role of dUTPase in their replication and pathogenesis is currently unknown.

Gene Deletion↗
PubMed2006

Reversal of HIV drug resistance and novel strategies to curb HIV infection: the viral infectivity factor Vif as a target and tool of therapy.

Due to the high genetic variability of human immunodeficiency virus (HIV), treatment of AIDS (acquired immunodeficiency syndrome) patients with inhibitors of reverse trancriptase (RT) and drugs blocking the viral protease regularly results in the accumulation of drug resistant HIV variants and treatment failure. The sensitivity of clinically derived resistant HIV-1 strains to nucleotide RT inhibitors could be restored, however, in several laboratories by pharmacological depletion of the appropriate endogenous deoxynucleotide triphosphate (dNTP), and such a manipulation (induction of dCTP pool imbalance during reverse transcription in the presence of a non-nucleoside RT inhibitor) altered the mutation spectrum of the HIV-1 genome, resulting in a lower level of HIV resistance to certain drugs. The cytoplasmic single-stranded DNA cytidine deaminases APOBEC3G and APOBEC3F block HIV replication by introducing premature stop codons into the viral genome. We suggest that the resulting crippled, defective HIV (dHIV) variants could interfere with replication of "wild type" viruses and curbe disese progression in long term non-progressor individuals. Vif, an accessory protein encoded by HIV, counteracts APOBEC3G/F action. We speculate that small molecule inhibitors of Vif could permit lethal or sublethal mutagenesis of HIV genomes. We suggest that an artificial dHIV construct carrying a mutated vif gene (coding for a Vif protein unable to block APOBEC3G/F) could have a therapeutic effect as well in HIV infected individuals and AIDS patients.

AIDS Vaccines↗
PubMed2002

The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration.

In the last five years there has been a rapid explosion of publications reporting that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in neurodegenerative disorders. Furthermore, there is a well-established loss of nAChRs in post-mortem brains from patients with Alzheimer's disease, Parkinson's disease and a range of other disorders. In the present review we discuss the evidence that nicotine and subtype selective nAChR ligands can provide neuroprotection in in vitro cell culture systems and in in vivo studies in animal models of such disorders. Whilst in vitro data pertaining to a protective effect of nicotine against nigral neurotoxins like MPTP is less robust, most studies agree that nicotine is protective against glutamate and beta-amyloid toxicity in various culture systems. This effect appears to be mediated by alpha7 subtype nAChRs since the protection is blocked by alpha-bungarotoxin and is mimicked by alpha7 selective agonists. In vivo studies indicate that alpha7 receptors play a critical role in protection from cholinergic lesions and enhancing cognitive function. The exact subtype involved in the neuroprotectant effects seen in animal models of Parkinson's disease is not clear, but in general broad spectrum nAChR agonists appear to provide protection, while alpha4beta2 receptors appear to mediate symptomatic improvements. Evidence favouring a protectant effect of nicotine against acute degenerative conditions is less strong, though some protection has been observed with nicotine pre-treatment in global ischaemia models. A variety of cellular mechanisms ranging from the production of growth factors through to inactivation of toxins and antioxidant actions of nicotine have been proposed to underlie the nAChR-mediated neuroprotection in vitro and in vivo. In summary, although the lack of subtype selective ligands has hampered progress, it is clear that in the future neuronal nAChR agonists could provide functional improvements and slow or halt the progress of several crippling degenerative diseases.

Acute Disease↗
PubMed1996

Aspergilloma in the paracavernous region--two case reports.

A 30-year-old male and a 40-year-old female presented with Aspergillus fungal granuloma in the cerebral locations involving the gasserian-ganglion and its divisions in one case and was densely adherent to the lateral dural wall of the cavernous sinus in the other. Both patients were otherwise healthy with no evidence of immuno-suppression. The lesions resembled benign tumor on preoperative imaging and intraoperative consistency and vascularity. The lesions were successfully and completely resected. Both patients developed major cerebral arterial territory infarcts in the postoperative phase, remote from the site of operation, leading to crippling neurological deficits in one patient and death in the other. The unusual location and the unusual and similar clinical course suggests that awareness of the possibility of ischemic complications after surgical resection of intracranial aspergillomas is necessary.

Adult↗
PubMed1977

Severe radiation injuries of the lung.

The lung is a radiosensitive organ whose limited tolerance must be treated with great respect in the radiation management of malignant tumors in the thorax. Severe radiation pneumonopathy can cripple and kill as the outcome of faulty judgment, error, accident, or calculated risk in an effort to control a locally advanced cancer. The clinical and radiologic profile of this unique and challenging syndrome is described and the histopathology and pathogenesis are reviewed. The clinical and technical factors of high risk are discussed, and guidelines for therapeutic management and safer clinical practice are offered.

Adrenal Cortex Hormones↗
PubMed1989

Age and sex differences in the responses of adolescents to the Hand Test.

The Hand Test of E. E. Wagner was administered to 163 adolescents attending a rural midwest high school. Subjects were placed into four age groups based on their chronological ages. There was an age difference for the variable Exhibition; however, post hoc analyses indicated that none of the age groups were significantly different from one another. Boys gave more Exhibition and Crippled responses, and interactions of age x sex in the absence of significant main effects were obtained for Direction, Tension and Environmental responses. Implications of the results are discussed.

Adolescent↗
PubMedDate not supplied

The meaning of life-threatening disease in the area of the head and neck.

The revelation that one has a life-threatening disease creates a sentient flood of emotions that infuse the patient with fear, confusion and depression. It contains the spectrum of pain, suffering, deterioration of life-style, crippling and possible annihilation. This burden falls first on the patient and his family, and then on his doctor. The drama is a dilemma of cure or palliation wrapped about the emotional core of that person with science, drugs, technology, mysticism and hope. The ongoing process is the most dynamic encounter of being alive, and before it is finished will have used and drained a large percentage of the vulnerable emotions that identify our humanness. An overview of these involvements as they relate to the area of the head and neck shows how complex the process has become, the remoteness of its solution and the truth of its experience.

Attitude to Death↗
PubMed1996

Gangrene of the penis due to strangulation by a metallic ring.

We present a case of a 32-year-old crippled patient who presented with gangrene of the penis due to strangulation by a magnetic metallic ring which is used to increase potency and prolong erection. The ring was removed and conservative treatment was tried for eight days but failed. Amputation of the penis was done was refashioning of the urethra at the tip of the stump.

Adult↗
PubMed1988

Future trends in the treatment of rheumatoid arthritis in the light of current etiopathogenetic theories.

The current treatment of rheumatoid arthritis is based on the use of synthetic chemical compounds, the mechanism and action of which have been more or less unknown. Usually this therapeutic effectiveness was discovered accidentally. Often the initial use of such compounds was motivated on the basis of generally diffuse ideas about the eventual pathogenesis of rheumatoid arthritis. The main site of action of most of these drugs has recently been elucidated. Depending on their multiple sites of action the polypharmacy frequency relied upon at present seems also to be theoretically motivated. Many new possibilities for treatment which have appeared recently have resulted from the amission of page limitation. These include various thymic (46), steroid and other hormones (67) and various vehicles or new modes of application, e.g. percutaneous, for directing the effects of drugs selectively to the target tissue, organ and cells. The use of specific T cell clones in therapy (68) has been only briefly dealt with in this article, and the development of operative techniques, endoprosthesis technology and orthopedic devices have not been dealth with at all. Chemical synovectomies with 165Dy-FHMA and other agents (69) will be developed further etc. This overview mainly deals with future trends in the treatment of rheumatoid arthritis based on advances made in the evaluation of the etiopathogenesis. Due to advances in basic sciences and medicine, the pathogenetic mechanisms effective in rheumatoid arthritis are better known today than ever before. The same progress in science has for the first time in history provided us with a potential means of producing bioactive mediators and reagents in sufficient amounts to enable their use also for therapeutic trials and treatment. In addition to the need to develop better methods of treatment for the patients crippled by this chronic disease, studies on the pathogenesis will also be of great benefit to our ideas about exactly what is involved in the complex process clinically known as rheumatoid arthritis.

Arthritis, Rheumatoid↗