Cryoneurolysis to treat the pain and symptoms of knee osteoarthritis: a multicenter, randomized, double-blind, sham-controlled trial.

OBJECTIVE: Evaluate the efficacy and safety/tolerability of cryoneurolysis for reduction of pain and symptoms associated with knee osteoarthritis (OA). DESIGN: Randomized, double-blind, sham-controlled, multicenter trial with a 6-month follow-up in patients with mild-to-moderate knee OA. Patients were randomized 2:1 to cryoneurolysis targeting the infrapatellar branch of the saphenous nerve (IPBSN) or sham treatment. The primary endpoint was the change from baseline to Day 30 in the Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain score adjusted by the baseline score and site. Secondary endpoints, including visual analogue scale (VAS) pain score and total WOMAC score, were tested in a pre-defined order. RESULTS: The intent-to-treat (ITT) population consisted of 180 patients (n = 121 active treatment, n = 59 sham treatment). Compared to the sham group, patients who received active treatment had a statistically significant greater change from baseline in the WOMAC pain subscale score at Day 30 (P = 0.0004), Day 60 (P = 0.0176), and Day 90 (P = 0.0061). Patients deemed WOMAC pain responders at Day 120 continued to experience a statistically significant treatment effect at Day 150. Most expected side effects were mild in severity and resolved within 30 days. The incidence of device- or procedure-related adverse events was similar in the two treatment groups with no occurrence of serious or unanticipated adverse device effects (ADE). CONCLUSIONS: Cryoneurolysis of the IPBSN resulted in statistically significant decreased knee pain and improved symptoms compared to sham treatment for up to 150 days, and appeared safe and well tolerated.

Blockade of the CD28 and CD40 pathways result in the acceptance of pig and rat islet xenografts but not rat cardiac grafts in mice.

Previously, we demonstrated that combination CTLA4-Fc and anti-CD40L mAb treatment results in tolerance to concordant, cellular islet xenografts. The aim of this study was to determine its effectiveness in a model of fetal pig pancreas (FPP) xenotransplantation. Survival of FPP fragment grafts were compared to the survival of rat islet or cardiac xenografts following short term CTLA4-Fc and anti-CD40L mAb treatment. Rat islet and FPP fragment grafts survived long-term. However, rat cardiac grafts were rejected by 52-91 days. Both rat islet and FPP grafts showed similar histology with intact islet structures and adjacent 'nests' of lymphocytes. Concordant vascularised rat hearts showed extensive polymorphonuclear infiltrate, concentric vasculitis and a perivascular infiltrate predominantly of CD8+ T cells. This suggests that this therapy is effective for prolonging islet xenografts and demonstrates that the cellular mechanism of rejection for vascularised and non-vascularised xenografts are different.

Use of antihypertensive and antithrombotic medications after stroke in community-based care.

BACKGROUND: Secondary stroke prevention strategies include pharmacologic approaches to control hypertension and reduce thromboembolic risk. OBJECTIVE: To describe antithrombotic and antihypertensive medication use, and rates of blood pressure control in the Kansas City Stroke Study, a prospective stroke cohort receiving community-based care after primarily mild and moderate stroke. METHODS: Participants from 12 area hospitals provided information about medication use prior to stroke. Study personnel measured blood pressures at enrollment and at one, three, and six months, and collected medication data at six months during in-home assessment. RESULTS: Complete data at six months were available for 355 subjects with ischemic stroke, among whom 13% had atrial fibrillation and 67% had prior hypertension. Prior to stroke, only 45% of the patients were receiving any antithrombotic (anticoagulant and/or antiplatelet) therapy; this figure rose to 77% at six months. Antithrombotic treatment rates among those with atrial fibrillation were 59% before stroke and 83% at six months, including warfarin in 64%. Approximately 70% of subjects had controlled blood pressures one, three, and six months after stroke, defined as systolic blood pressure < or = 140 mm Hg and diastolic blood pressure < or = 90 mm Hg. Use of multiple antihypertensive agents was common; calcium-channel blockers and angiotensin-converting enzyme inhibitors were used most frequently. However, 19% of subjects with uncontrolled blood pressure were untreated at six months. CONCLUSIONS: Although room for improvement remains, these data suggest improved rates of antithrombotic and antihypertensive medication use after stroke in community-based care in a midwestern metropolitan community, compared with previous reports.

Disability evaluation following stroke.

The physician performing a disability evaluation needs to document the stroke patient's impairments carefully. This is achieved through a thorough history, physical examination, and if necessary, neuropsychologic assessment. Most often, the clinician will deal with the Social Security Administration system; however, the physician may occasionally need to provide this information for private disability insurance.

Inducible nitric oxide synthetase is expressed in adult but not fetal pig pancreatic islets.

Cytokine-induced expression of inducible nitric oxide synthetase (iNOS) and production of nitric oxide (NO) by pancreatic islet cells has been suggested as one potential mechanism for beta cell destruction. In this study, we investigated the role of iNOS and NO in islet primary non-function. Islets were assessed for their function, viability and expression of iNOS. Adult rat and pig islets isolated by collagenase digestion and fetal pig pancreas (FPP) grafts isolated by collagenase digestion or high oxygen culture were transplanted into C57BL6 mice and nude mice. iNOS protein was detected by immunohistochemistry. iNOS protein was found in normal rat and pig pancreas and adult rat and pig islets that were isolated by collagenase digestion and transplanted into either C57BL6 mice or nude mice. iNOS was not detected in fetal pig islet grafts, regardless of whether collagenase was used in the isolation process. In adult pig islet grafts, the presence of iNOS protein correlated with high levels of islet cell apoptosis and primary non-function. Despite the persistent presence of iNOS in rat islets, there was no evidence that it had a deleterious effect on rat islet viability, or function. Therefore, in isolated adult pig islets, there was a correlation between iNOS expression and apoptosis, suggesting that iNOS activation may be deleterious to the adult pig islets. However, other factors such as the fragility of the islet capsule may be equally important. By contrast, fetal pig islets did not express iNOS and this may be an important reason for their enhanced viability when compared with adult islet tissue.

The relation between impairments and functional outcomes poststroke.

OBJECTIVE: To assess the influence of initial stroke impairments on the severity of basic and higher level functional deficits over time and to determine the cumulative impact on functional deficits beyond severity of motor deficits alone. DESIGN: Observational study. SETTING: Twelve participating hospitals in the Greater Kansas City area, as part of the Kansas City Stroke Study (October 1995-March 1998). PARTICIPANTS: Individuals (n = 459) who sustained an eligible stroke were evaluated prospectively using standardized assessments at enrollment (within 14 days of stroke onset, 8.8 +/- 3.5 days). MAIN OUTCOME MEASURES: Mobility and activities of daily living (ADLs) were assessed at 1, 3, and 6 months poststroke using the Functional Independence Measure, Barthel index, Lawton Instrumental Activities of Daily Living (IADL), and the Medical Outcomes Study Short-Form Health Survey instruments. RESULTS: The cumulative probability of achieving independence with walking, a Barthel index of 60 or greater or 90 or greater, and independence in 3 or more IADL was significantly different for the following 4 impairment groups in descending order: motor; motor and somatosensory; motor and hemianopia; and motor, sensory, and hemianopia. Although motor severity was a strong predictor of outcome (p < .0001), the additional somatosensory and hemianopia deficits significantly (p < .05) affected time and likelihood of achieving these levels of function. CONCLUSION: Cumulative deficits poststroke affect patients' functional outcome in the first 6 months poststroke beyond the effect of motor severity alone.

Diagnosis and management of acute low back pain.

Acute low back pain is commonly encountered in primary care practice but the specific cause often cannot be identified. This ailment has a benign course in 90 percent of patients. Recurrences and functional limitations can be minimized with appropriate conservative management, including medications, physical therapy modalities, exercise and patient education. Radiographs and laboratory tests are generally unnecessary, except in the few patients in whom a serious cause is suspected based on a comprehensive history and physical examination. Serious causes that need to be considered include infection, malignancy, rheumatologic diseases and neurologic disorders. Patients with suspected cauda equina lesions should undergo immediate surgical investigation. Surgical evaluation is also indicated in patients with worsening neurologic deficits or intractable pain that is resistant to conservative treatment. The current recommendation is two or three days of bed rest for patients with acute radiculopathy. The treatment plan should be reassessed in patients who do not return to normal activity within four to six weeks.

A large-animal model to evaluate the clinical potential of fetal pig pancreas fragment transplantation.

The long-term goal of this study is to assess the feasibility of using fetal pig pancreas fragment (FPPF) transplantation to treat patients with type I diabetes. Using the highly inbred Westran Pigs, our initial aim was to establish a rejection-free transplant model of FPPF grafted into sibling recipient pigs without immunosuppression. FPPFs were isolated from 80-100-day-old fetuses of either Westran Pigs or outbred pigs and transplanted into the thymus, spleen, liver, or kidney of the recipient Westran pig. Biopsies were taken from each transplant site at set time points and assessed histologically for islet viability, rejection, and endocrine function. Fifty-eight fetal donors were used to transplant 16 recipient pigs. A nonspecific inflammation was seen for both outbred and inbred FPPF donor tissue at day 3 and was considered a response to ischemic necrosis. However, all the transplanted outbred FPPF donor tissue was acutely rejected and lost by day 10-14. In contrast, inbred FPPF tissue showed little evidence of graft necrosis after 3 days, and growth and formation of epithelial islet cell nest-like structures were seen to 28 days after transplantation. With time after transplantation, increasing amounts of insulin immunoperoxidase staining was seen together with chromogranin and somatostatin staining. In summary, this study confirms the potential of the Westran pig to answer the unproven ability of fetal pancreatic tissue to reverse type I diabetes in a large animal model.

Induction of allogeneic islet tolerance in a large-animal model.

For islet allotransplantation to become a therapy widely applicable to patients with insulin-dependent diabetes, it will be important to avoid conventional immunosuppression and yet maintain long-term rejection-free islet survival. This possibility was tested in a large-animal model using mixed allogeneic chimeras established using total lymphoid irradiation (TLI) and donor-specific bone marrow transplantation (BMTX). Four recipient sex-mismatched and DLA class II-matched English springer spaniels became chimeric after TLI and donor-specific BMTX. Subsequent donor-specific renal allografts survived for more than a year. Acceptance of a donor-specific skin graft and rejection of a third-party graft demonstrated tolerance with maintenance of immunocompetence. Pancreatic microfragments containing islets were refluxed into the splenic vein of the recipient. Purified islets were placed under the capsule of spleen and liver. After 75 days, recipients underwent total native pancreatectomy. All four chimeric pancreatectomized dogs had functioning islet grafts 75 days after transplantation, evidenced by a prompt rise in serum insulin levels following an IVGTT and histological demonstration of islet tissue at the site of transplantation. After removal of the transplanted islet tissue, no insulin was released after IVGTT. In summary, intrasplenic allogeneic canine islets transplanted into chimeric dogs rendered tolerant to donor MHC survive and function for greater than 75 days in the absence of immunosuppression. This study represents proof of the concept that allogeneic islet transplants have the potential to reverse diabetes without the use of conventional immunosuppression.

Cloning of BY55, a novel Ig superfamily member expressed on NK cells, CTL, and intestinal intraepithelial lymphocytes.

Expression of the BY55 protein has been shown to be tightly associated with NK and CD8+ T lymphocytes with cytolytic effector activity. To determine the function of this protein, we molecularly cloned BY55 cDNA. The cDNA sequence predicts a cysteine-rich, glycosylphosphatidylinositol-anchored protein of 181 amino acids with a single Ig-like domain weakly homologous to killer inhibitory receptors. Reduction and carboxyamidomethylation of immunoprecipitated BY55 gave a band of 27 kDa, whereas reduction alone led to an 80-kDa species, suggesting that BY55 is a tightly disulfide-linked multimer. RNA blot analysis revealed BY55 mRNAs of 1.5 and 1.6 kb whose expression was highly restricted to NK and T cells. BY55 was expressed on the CD56dim, CD16+ subset of NK cells, which have high cytolytic activity, but was not expressed and was not induced on the CD56bright, CD16-subset of NK cells, a subset with high proliferative, but low cytolytic, capacity. In human tissues, BY55 mRNA was expressed only in spleen, PBL, and small intestine (in gut lymphocytes). BY55 was expressed on all intestinal intraepithelial lymphocytes, which were predominantly CD3+TCRalpha/beta+CD4-CD8+CD11b+CD28-CD45RO+C D56-CD101+CD103+ (alphaEbeta7 integrin). In addition, BY55 was expressed on most CD8+CD28- peripheral blood T cells. These phenotypic relationships suggest that CD8+CD28+ precursor CTL may terminally differentiate into CD8+CD28-BY55+ effector CTL and that some of the peripheral blood CD8+CD28- subset may represent recirculation from mucosal epithelial immune sites.

Biological properties of the angiotensin-converting enzyme inhibitor cilazapril.

Cilazapril is the monoethyl ester prodrug form of a potent, specific. long-acting antihypertensive inhibitor of angiotensin-converting enzyme (ACE). The biochemical and pharmacological properties of this compound have been compared with those of captopril and enalapril. In all test systems, cilazapril was the most potent and the longest acting. The active diacid of cilazapril was more potent than the corresponding diacid of enalapril in inhibiting the cleavage of angiotensin I and of Hip-His-Leu by ACE in vitro, in antagonising the angiotensin I-induced contractions of the isolated ileum of the guinea pig, in potentiating the vasodepressor responses to bradykinin, and in reducing the angiotensin I-induced rise in blood pressure of the rat. Parent drug absorption and diacid bioavailability in the rat were higher than for enalapril, and the inhibition of plasma ACE of longer duration. Single doses of cilazapril were more potent than enalapril in lowering the blood pressure of spontaneously hypertensive rats (SHR) and two-kidney renal hypertensive rats. On repeated daily oral dosing to SHR, both compounds had a cumulative antihypertensive effect. The acute antihypertensive effect was enhanced by simultaneous treatment with hydrochlorothiazide.

Method for measuring the duration of inhibition of angiotensin I-converting enzyme in vivo.

The spontaneously hypertensive rat, either pithed or anesthetized with urethane, responds to intravenous injections of angiotensin I (A1) and angiotensin II (AII) with pressor responses. These responses vary with time, but the ratio of the responses to AI and AII is constant throughout 4.5 hr. This criterion was used to determine the degree and the duration of effect of captopril. At low (30 micro g/kg iv) and high (3mg/kg iv) doses, it selectively reduces the pressor response to AI, so reducing the AI/AII ratio. The rate of recovery is initially rapid followed by a prolonged slower phase. The degree (maximum 65%) and the duration of inhibition are directly related to the dose of the inhibitor.