Humoral and T-cell responses to SARS-CoV-2 vaccination in multiple sclerosis patients treated with ocrelizumab.

BACKGROUND: The COVID-19 epidemic raises important questions about the efficacy of vaccines for people treated with ocrelizumab, an anti-CD20 therapy. Ocrelizumab has been shown to reduce the humoral response to SARS-CoV-2 infection and vaccination, but the T-cell response to vaccination has not been fully characterized. We sought to provide data regarding B and T-cell mediated responses to SARS-CoV-2 vaccination in ocrelizumab-treated patients, and to determine what variables correlate with vaccine immunogenicity. We hypothesized that patients without a humoral response to SARS-CoV-2 vaccination would still have intact T-cell responses. METHODS: We conducted a prospective, observational, single center cohort study of patients with MS treated with either ocrelizumab or natalizumab as a comparator between March 2, 2021, and July 1, 2021. Eligible patients were age 18 to 55 and had no known prior infection with, or vaccination against, SARS-CoV-2. Patients with prior use of immunosuppressive or chemotherapeutic agents, or treatment with any anti-CD20 therapy other than ocrelizumab within 12 months of enrollment, were excluded. The Roche Elecsys anti-SARS-CoV-2 S immunoassay was performed prior to and 3-4 weeks post vaccination to evaluate the antibody response to SARS-CoV-2 spike IgG. The Adaptive Biotechnologies T-Detect COVID Test was performed to evaluate the adaptive T-cell immune response to SARS-CoV-2 in OCR-treated patients with no detectable antibodies. Data were analyzed using descriptive statistics, Fisher's exact test, and Wilcoxon rank sum. RESULTS: Forty-eight patients were enrolled in the study, 69% treated with ocrelizumab and 31% treated with natalizumab. Eighteen percent of ocrelizumab and 100% of natalizumab patients had a positive antibody response. In ocrelizumab-treated patients, there was no correlation between age, sex, BMI, total number of infusions, immunoglobulin G, CD19, or absolute lymphocyte count and antibody response. There was a trend suggesting that a longer interval between the last infusion and vaccination increased the likelihood of producing antibodies (P = 0.062). All ocrelizumab patients with negative antibody responses had positive T-cell responses. CONCLUSIONS: Treatment with ocrelizumab substantially impaired the humoral response to SAR-CoV-2 vaccination but did not impair T-cell responses. Further research is needed to determine if the T-cell response to SARS-CoV-2 vaccination is sufficient to prevent infection or reduce severity of COVID in patients who did not produce antibodies.

T helper 2 (Th2) T cells induce acute pancreatitis and diabetes in immune-compromised nonobese diabetic (NOD) mice.

Autoimmune diabetes is caused by the CD4(+), T helper 1 (Th1) cell-mediated apoptosis of insulin-producing beta cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.

In autoimmune diabetes the transition from benign to pernicious insulitis requires an islet cell response to tumor necrosis factor alpha.

The islet-infiltrating and disease-causing leukocytes that are a hallmark of insulin-dependent diabetes mellitus produce and respond to a set of cytokine molecules. Of these, interleukin 1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma are perhaps the most important. However, as pleiotropic molecules, they can impact the path leading to beta cell apoptosis and diabetes at multiple points. To understand how these cytokines influence both the formative and effector phases of insulitis, it is critical to determine their effects on the assorted cell types comprising the lesion: the effector T cells, antigen-presenting cells, vascular endothelium, and target islet tissue. Here, we report using nonobese diabetic chimeric mice harboring islets deficient in specific cytokine receptors or cytokine-induced effector molecules to assess how these compartmentalized loss-of-function mutations alter the events leading to diabetes. We found that islets deficient in Fas, IFN-gamma receptor, or inducible nitric oxide synthase had normal diabetes development; however, the specific lack of TNF- alpha receptor 1 (p55) afforded islets a profound protection from disease by altering the ability of islet-reactive, CD4(+) T cells to establish insulitis and subsequently destroy islet beta cells. These results argue that islet cells play a TNF-alpha-dependent role in their own demise.

The SJL/J T cell response to both spontaneous and transplantable syngeneic reticulum cell sarcoma is mediated predominantly by the V beta 17a+ T cell clonotype.

Previous studies have revealed that the reticulum cell sarcoma (RCS) of SJL/J (H-2s, IE-) mice express an "IE-like" stimulatory tumor-associated antigen, the expression of which is requisite for stimulating host T cells necessary for tumor growth. Herein, we present evidence that the predominant T cells raised in the syngeneic response to both spontaneous and transplantable RCS tumors are of the V beta 17a TCR clonotype. The V beta 17a+ clonotype of T cells has been shown to interact with IE allogeneic specificities. We demonstrate that all four characterized RCS-specific T cell hybridomas stained positively for the anti-V beta 17a mAb, KJ23a. Additionally, KJ23a, when added to cocultures of the T cell hybridomas and RCS tumors, inhibited the release of IL-2 by the hybridomas. Further, KJ23a was shown to markedly inhibit the proliferation of SJL/J T cells when cocultured with either spontaneous or transplantable RCS tumor cells. When analyzed by flow cytometry, the T cell blast population raised in response to both spontaneous and transplantable RCS were greater than 80% KJ23a+. These T cells were brightly stained by the anti-CD4 mAb, Gk1.5, and, therefore, represent class II-responsive T cells. In corroboration of the in vitro data, T cells derived from mesenteric lymph nodes of RCS tumor-bearing mice had likewise undergone a similar expansion of V beta 17a+, CD4+ T cells. Together, these results indicate that KJ23a+ T cells play an important and predominant role in the response of SJL/J mice to spontaneous RCS tumors and provide further suggestive evidence that the stimulatory antigen(s) on the RCS tumor is IE or an "IE-like" molecule. Significantly, the important role V beta 17a+ T cells play in the response to RCS suggests a potential therapeutic role for KJ23a mAb in the intervention and prevention of RCS tumors in SJL/J mice.

T helper cell subsets in insulin-dependent diabetes.

It has been proposed that the development of insulin-dependent diabetes is controlled by the T helper 1 (TH1) versus TH2 phenotype of autoreactive TH cells: TH1 cells would promote diabetes, whereas TH2 cells would actually protect from disease. This proposition was tested by establishing cultures of TH1 and TH2 cells that express an identical diabetogenic T cell receptor and comparing their ability to initiate disease in neonatal nonobese diabetic mice. TH1-like cells actively promoted diabetes; TH2-like cells invaded the islets but did not provoke disease--neither did they provide substantial protection.

Interleukin-4 deficiency does not exacerbate disease in NOD mice.

To investigate the role of interleukin (IL)-4 in the regulation of autoimmune diabetes, we crossed the IL-4 knock-out mutation onto the NOD genetic background. This experiment was accelerated by typing for microsatellites linked to known diabetes susceptibility (Idd) loci, and included a control backcross of the wild-type 129/SvJ-derived IL-4 gene, the original target locus. We also crossed the mutation into the BDC2.5 transgenic line, a diabetes model that carries the rearranged T-cell receptor genes from a diabetogenic T-cell clone. The IL-4-null mutation did not accelerate or intensify insulitis in regular NOD mice or in the BDC2.5 transgenic model; it also had no effect on the timing or frequency of the transition to overt diabetes. These data indicate that IL-4 plays no required role in controlling the aggressiveness of murine diabetes.

Emergency coronary angioplasty for acute myocardial infarction. Results from a community hospital.

Emergency coronary angioplasty was performed in 127 patients presenting to a community hospital with acute myocardial infarction. Reperfusion and successful dilatation were performed in 117 patients (92%) at 3.3 +/- 1.8 hours from the onset of pain. Eleven patients (8.6%) died, ten patients (7.9%) developed reocclusion, and ten patients (7.9%) required coronary bypass surgery during the initial hospitalization. Late restenosis occurred in 36% (27/76) of patients restudied or 27% (27/100) of patients at risk for restenosis. Ejection fraction improved in patients with patent vs occluded vessels (8.4% +/- 8.2% vs -4.1% +/- 6.0%) and improved most in anterior vs inferior vs posterolateral infarcts (11.0% +/- 8.4% vs 6.8% +/- 6.4% vs 2.6% +/- 7.5%). Posthospitalization follow-up in all patients (mean, 13.4 months) revealed only one late death. Of the patients followed up, 83% had no angina, and 17% of patients had mild angina. Our experience demonstrates that coronary angioplasty for acute myocardial infarction can be performed in the community hospital by an experienced cardiovascular laboratory team with a high success rate, a low reocclusion rate, an improvement in ejection fraction, and an excellent long-term prognosis. The community hospital setting allows early access to patients and creates the potential for early reperfusion and myocardial salvage.

Progressive necrotic myelopathy: clinical course in 9 patients.

OBJECTIVE: To review the clinical, laboratory, and radiological findings of 9 patients who had progressive idiopathic myelopathy with evidence of spinal cord necrosis. DESIGN AND METHODS: We reviewed personally examined cases of myelopathy that fulfilled the following criteria: (1) regional loss of reflexes, flaccidity, and muscle atrophy; (2) magnetic resonance imaging showing a shrunken or cavitated cord without evidence of arteriovenous malformation; (3) electromyogram showing denervation over several contiguous spinal cord sgements with preservation of sensory potentials in some cases; and (4) the absence of evidence of systemic disease or neoplasm. RESULTS: The illness began in these patients after the age of 40 years, with prominent burning or tingling limb pain, occasionally with radicular features or with less well-defined back, neck, or abdominal pain. Leg or infrequently arm weakness appeared concurrently or soon after the onset of pain. The most distinctive feature was a saltatory progression of symptoms, punctuated by both acute and subacute worsenings approximately every 3 to 9 months, culminating in paraplegia or tetraplegia. The distinguishing clinical findings, together indicative of destruction of gray matter elements of the cord, were limb atrophy, persistent areflexia, and flaccidity. The concentration of cerebrospinal fluid protein was typically elevated between 500 g/L and 1000 g/L, without oligoclonal bands, accompanied infrequently by pleocytosis. Magnetic resonance imaging showed features suggesting cord necrosis, specifically swelling, T2-weighted hyperintensity, and gadolinium enhancement over several spinal cord segments, succeeded months later by atrophy in the same regions. Necrosis of the cord was found in biopsy material from one patient and postmortem pathology in another case, but inflammation and blood vessel abnormalities were absent. Only 2 patients had prolonged visual evoked responses. The disease progressed despite immune-modulating treatments although several patients had brief epochs of limited improvement. CONCLUSIONS: The saltatory course, prolonged visual evoked responses in 2 patients, and a cranial abnormality on magnetic resonance imaging in another, raised the possibility of a link to multiple sclerosis. However, the normal cranial magnetic resonance imaging scans in 6 other patients, uniformly absent oligoclonal bands, and poor response to treatment were atypical for multiple sclerosis. On the basis of shared clinical and laboratory features, idiopathic progressive necrotic myelopathy is indistinguishable from a limited form of Devic disease.

A case of Balamuthia mandrillaris meningoencephalitis.

Balamuthia mandrillaris is a newly described pathogen that causes granulomatous amebic encephalitis, an extremely rare clinical entity that usually occurs in immunosuppressed individuals. We report a case of pathologically proven Balamuthia encephalitis with unusual laboratory and radiologic findings. A 52-year-old woman with idiopathic seizures and a 2-year history of chronic neutropenia of unknown cause had a subacute illness with progressive lethargy, headaches, and coma and died 3 months after the onset of symptoms. Cerebrospinal fluid (CSF) glucose concentrations were extremely low or unmeasurable, a feature not previously described (to our knowledge). Cranial magnetic resonance imaging scans showed a single large temporal lobe nodule, followed 6 weeks later by the appearance of 18 ring-enhancing lesions in the cerebral hemispheres that disappeared after treatment with antibiotics and high-dose corticosteroids. The initial brain biopsy specimen and analysis of CSF samples did not demonstate amebae, but a second biopsy specimen and the postmortem pathologic examination showed Balamuthia trophozoites surrounded by widespread granulomatous inflammation and vasculitis. The patient's neutropenia and antibiotic use may have caused susceptibility to this organism. Amebic meningoencephalitis should be considered in cases of subacute meningoencephalitis with greatly depressed CSF glucose concentrations and multiple nodular lesions on cerebral imaging. Arch Neurol. 2000;57:1210-1212

Receptors for C3b on the neutrophil surface associate with the cytoskeleton-containing cell residue subsequent to cell lysis with non-ionic detergent. Cytoskeletal-CR1 interactions.

Radioiodinated Fab' and F(ab')2 fragments were prepared from 57F monoclonal antibody which is specific for the C3b receptor (CR1) on human cells. We find that both Fab' and F(ab')2 fragments bind to CR1 on human neutrophils and then dissociate, at 0 degree C, with half-lives of 172 and 35 min, respectively. In addition to binding to cell surface CR1, both antibody fragments bind specifically to the isolated non-ionic detergent-insoluble cellular residue (NDIR) which remains after cell lysis and solubilization in Triton X-100. We also find that Fab' and F(ab')2 antibody fragments remain associated with the NDIR after the radiolabeled antibody fragments are allowed to bind to cell surface CR1, the unbound fragments removed, and the cells subsequently lysed in non-ionic detergent. Because the cytoskeletal matrix (together with the cell nucleus) makes up a substantial portion of the NDIR, these results suggest that some fraction of cell surface CR1 may be associated in vivo with the cytoskeletal matrix. However, post-lysis association of cell surface-CR1-antibody fragment complexes to the NDIR occurs. Examination of the binding kinetics of this interaction reveals that less than 10% of cell surface CR1 exists bound to the NDIR prior to cell lysis. While the nature of post-cell lysis association of CR1 with the NDIR is unknown, several modulating effects are noted. For example, binding of bivalent cross-linking agents to CR1 on cells followed by a 37 degrees C incubation is known to induce internalization of cell surface CR1. We find that binding of F(ab')2 antibody fragments under these conditions causes a 50% decrease in association of this 57F fragment to the NDIR. Pretreatment of the cells at 37 degrees C with the chemotactic peptide N-formyl-methionyl-leucylphenylalanine similarly caused a 50% decrease of (Fab'-labeled) CR1 association with the NDIR cell fraction. These results support the hypothesis that chemotactic peptide serves to enhance CR1-mediated adherence to C3b-bearing targets by increasing the density of CR1 on the cell surface rather than by inducing cytoskeletal-dependent, detergent-stable, CR1 redistribution on the cell surface.

Benefit of late coronary reperfusion in patients with acute myocardial infarction and persistent ischemic chest pain.

The benefit of thrombolytic therapy given late after the onset of acute myocardial infarction (AMI) has been controversial because of low reperfusion rates and limited myocardial salvage. Persistent chest pain has been used as a criteria for late intervention, but there is little documentation to validate this practice. Clinical outcomes and myocardial salvage were evaluated in 74 patients with AMI and persistent chest pain who underwent late reperfusion (> 6 hours) with direct coronary angioplasty, and these were compared with outcomes in 460 patients with early reperfusion (< or = 6 hours). Patients with late reperfusion had a high infarct artery patency rate (96%), a low hospital mortality rate (5.4%), and a low incidence of reinfarction (1.4%) and recurrent ischemia that were similar to patients with early reperfusion. Patients with late reperfusion had surprisingly good recovery of left ventricular function with improvement in ejection fraction from 50% to 60% at follow-up angiography. Patients with late reperfusion had a greater incidence of collateral flow (45% vs 22%, p < 0.001) and a lower value of peak creatine kinase (1,357 vs 2,057 U/liter, p < 0.001) than patients with early reperfusion. This study emphasizes the importance of persistent chest pain as a marker of continued myocardial viability in patients who present late after AMI. These data suggest that the probable mechanism of continued viability is preserved flow to the infarct zone. Patients with AMI and persistent chest pain may benefit from reperfusion therapy beyond 6 to 12 hours.

Outcomes of direct coronary angioplasty for acute myocardial infarction in candidates and non-candidates for thrombolytic therapy.

Coronary angioplasty without prior thrombolytic therapy was performed in 383 patients with acute myocardial infarction (AMI). Patients were divided into 2 groups depending on whether they were candidates or non-candidates for thrombolytic therapy. Patients were not considered thrombolytic candidates if they: (1) presented in cardiogenic shock, (2) were greater than or equal to 75 years of age, (3) had had coronary artery bypass surgery or, (4) had a reperfusion time of greater than 6 hours. Thrombolytic and nonthrombolytic candidates had similar rates of reperfusion (92 vs 88%), nonfatal reinfarction (6.0 vs 5.9%) and recurrent myocardial ischemia (1.8 vs 0%). Thrombolytic candidates had a lower mortality rate (3.9 vs 24%, p less than 0.0001) and a lower incidence of bleeding (4.6 vs 10.9%, p less than 0.05). Improvement in left ventricular ejection fraction at follow-up angiography was 4.4% in thrombolytic and 10.5% in nonthrombolytic candidates (p less than 0.002). Ejection fraction improved most in patients with anterior wall AMI (7.7% in thrombolytic candidates, 15.1% in nonthrombolytic candidates) and in patients with reperfusion times greater than 6 hours (14.2%). These outcomes suggest that direct coronary angioplasty is a viable alternative method of reperfusion in patients with AMI who are candidates for thrombolytic therapy. Nonthrombolytic candidates are a high-risk group of patients. Direct coronary angioplasty may be beneficial in certain subgroups, especially for patients in cardiogenic shock and for patients presenting greater than 6 hours after the onset of chest pain with evidence of ongoing ischemia.

Importance of a patent infarct-related artery for hospital and late survival after direct coronary angioplasty for acute myocardial infarction.

The importance of a patent infarct-related artery (IRA) for hospital and late survival was examined in 383 patients with acute myocardial infarction treated with direct coronary angioplasty. At hospital discharge, 317 of 348 patients (91%) had a patent IRA and mean follow-up left ventricular (LV) ejection fraction (EF) was 58%. Cardiac survival after hospital discharge at 1, 3 and 6 years was 99, 95 and 90%. Patency of the IRA was the most important determinant of hospital mortality: patent versus occluded IRA, 5 vs 39% mortality, p less than 0.001. Follow-up LVEF was the most important determinant of late cardiac mortality: follow-up LVEF greater than or equal to 45 versus less than 45%, 2 versus 24% mortality, p less than 0.001. Patency of the IRA was not a significant predictor of late cardiac mortality in the group as a whole: patent versus occluded IRA, 4.7 versus 6.5% mortality, p = 0.67. In the subgroup of patients with depressed initial LVEF less than 45%, patency was a significant predictor of late cardiac mortality: patent versus occluded IRA, 9.2 versus 40% mortality, p = 0.03. Patients with a patent IRA had better recovery of LV function than patients with an occluded IRA (follow-up LVEF 58.5 versus 47.6%, p less than 0.001). When late cardiac mortality was adjusted for differences in follow-up LVEF, patency was no longer a significant predictor of late mortality. Our results indicate patency of the IRA is the most important determinant of hospital survival, and LV function (measured after recovery) is the most important determinant of late cardiac survival.(ABSTRACT TRUNCATED AT 250 WORDS)

A long-term dose-response study of mitomycin in glaucoma filtration surgery.

OBJECTIVE: To establish the long-term, dose-response relationship between the concentration of and duration of exposure to mitomycin to a decrease in intraocular pressure (IOP) and fewer complications. METHODS: We performed a prospective double-masked, placebo-controlled, 1-year study evaluating the decrease in IOP and fewer complications of fornix-based trabeculectomy surgery in 300 eyes equally divided among therapy with placebo; mitomycin, 0.2 mg/ mL, applied for 2 minutes; mitomycin, 0.4 mg/mL, applied for 4 minutes; or mitomycin, 0.4 mg/mL, applied for 2 minutes. All of the eyes had vertical and horizontal cup-disc ratios greater than 0.7. RESULTS: We observed significant treatment-related differences in IOP, with a decrease in IOP in all 3 mitomycin-treated groups for all of the times beyond 1 month. The number of eyes achieving strict IOP control and the development of cataract suggest a possible dose-response effect for concentration and time of exposure. Progressive lens opacification was the most frequent complication in 54 eyes (18.1%). The incidence of progressive lens changes markedly increased in subjects receiving 4 minutes of mitomycin therapy. Cataract formation was unrelated to IOP. Other complications were rare. Macular folds developed in 6 patients, with visual acuity returning to better than 20/40 in all but 1 patient. CONCLUSIONS: A possible dose-response relationship seemed to exist between the concentration of and duration of exposure to mitomycin. Length of exposure seems to be more important than concentration. The benefits of additional decreases in IOP must be weighed against the potential for increases in the risk of complications.

Synthesis of the C16-C28 spiroketal subunit of spongistatin 1 (altohyrtin A): the pyrone approach.

The synthesis of the CD spiroketal fragment of spongistatin 1 (altohyrtin A) has been accomplished utilizing the addition of a metalated pyrone to an aldehyde and subsequent acid-catalyzed spirocyclization. A stereoselective hydrogenation and subsequent conformational inversion establish the C19 stereocenter and the axial-equatorial spiroketal center.

Diastereoselective alkylations of oxazolidinone glycolates: a useful extension of the Evans asymmetric alkylation.

[reaction: see text] The diastereoselective alkylation of glycolate oxazolidinones has been demonstrated as a method for the enantioselective preparation of alpha-alkoxy carboxylic acid derivatives and selectively protected 1,2-diols. Various protecting groups on the glycolate hydroxyl and multiple substitution patterns on allylic iodides are tolerated in the alkylation. Yields for the alkylations are typically 70-85% with diastereoselectivities of >98:2.

An aldol approach to the synthesis of the EF fragment of spongistatin 1.

A synthesis of the C29-C51 fragment of spongistatin 1, containing the E and F rings, has been completed. The approach relies on four diastereoselective aldol additions and an asymmetric glycolate alkylation to establish eight of the eleven stereogenic centers. The intact chlorodiene side chain was appended by a Lewis acid catalyzed addition of an allylstannane to an epoxy enol ether.

Early extubation following pediatric cardiothoracic operation: a viable alternative.

A protocol is presented that facilitates early extubation following pediatric cardiothoracic operations. A total of 197 consecutive patients were managed according to this protocol. Fifty percent of the patients were less than 3 years old. Cardiopulmonary bypass was required in 113 (57%) of the surgical procedures. Extubation immediately following the surgical procedure was accomplished in 142 (72%) of the patients. Pulmonary complications occurred in 8 of these 142 patients (6%) and in 10 (18%) of the 55 patients requiring postoperative mechanical ventilation. Of the patients having early extubation, 5 (4%) required reintubation. One death in this group was unrelated to pulmonary function. There were 16 deaths among the 55 patients managed with mechanical ventilation. Carefully conducted early extubation provided specific advantages over routine postoperative mechanical ventilation. Modern techniques of anesthesia and surgical repair of congenital heart disease can decrease the requirement for postoperative mechanical ventilation and the potential for related complications.

Bioavailability of digoxin capsules and tablets: effect of coadministered fluid volume.

The effect of different coadministered fluid (water) volumes on the consistency of digoxin absorption was studied in 16 male volunteers. Each volunteer received four single-dose treatments (two 0.25-mg digoxin tablets with 30- and 240-mL of water and two 0.2-mg digoxin capsules with 30- and 240-mL of water). Digoxin present in serum and urine samples collected for 48 h after dosing was quantified by RIA. Treatments were compared by evaluating the following model-independent pharmacokinetic parameters: maximum serum concentration (Cmax); time of maximum serum concentration (tmax); area under the serum concentration-time curve for 0-12 h (AUC0-12); cumulative urinary excretion for 0-48 h (CUE48). No significant differences were found between dosage form (tablets versus capsules) and coadministered water volume (30 mL versus 240 mL) for any of the parameters. For both fluid volumes the AUC0-12 and Cmax were significantly larger (p less than 0.01) and the tmax significantly shorter (p less than 0.01) for the capsules than for the tablets. The volume of coadministered water had no effect on the amount of digoxin absorbed from either dosage form.

Familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an inherited multisystem disease manifested by painful, febrile attacks affecting the chest, abdomen, joints, and skin. No simple studies confirm the presence of FMF, contributing to the difficulty in diagnosis. A 10-year-old boy initially presented with a diffuse rash and complaints of bilateral joint pain of the hips, knees, and ankles and pain of the right shoulder. The child responded to daily naproxen. One year later, he continued to complain of hip, knee, ankle, and bilateral wrist pain. He also reported mild to moderate recurrent abdominal discomfort. Omeprazole provided intermittent relief. The patient continued to experience episodes of joint and abdominal pain. Two and a half years after he first presented, FMF was considered. In the second case, a 51-year-old man presented to the emergency department with complaints of fever, cough, and abdominal and joint pain. Fever, joint pain, and swelling decreased during the next few days. The patient was maintained on colchicine, with complete resolution of joint pain complaints during the next few days. Colchicine, 1 to 2 mg per day taken continuously during flare and quiescent periods, is the treatment of choice for FMF. Colchicine reduced the severity and frequency of attacks and may also delay or prevent secondary amyloidosis.