Association of prior treatment with nitrogen-containing bisphosphonates on outcomes of COVID-19 positive patients.

COVID-19 infection has resulted in significant morbidity and mortality globally, especially among older adults. Repurposed drugs have demonstrated activity in respiratory illnesses, including nitrogen-containing bisphosphonates. In this retrospective longitudinal study at 4 academic medical centers, we show no benefit of nitrogen-containing bisphosphonates regarding ICU admission, ventilator use, and mortality among older adults with COVID-19 infection. We specifically evaluated the intravenous bisphosphonate zoledronic acid and found no difference compared to oral bisphosphonates. BACKGROUND: Widely used in osteoporosis treatment, nitrogen-containing bisphosphonates (N-BP) have been associated with reduced mortality and morbidity among older adults. Based on prior studies, we hypothesized that prior treatment with N-BP might reduce intensive care unit (ICU) admission, ventilator use, and death among older adults diagnosed with COVID-19. METHODS: This retrospective analysis of the PCORnet Common Data Model across 4 academic medical centers through 1 September 2021 identified individuals age >50 years with a diagnosis of COVID-19. The composite outcome included ICU admission, ventilator use, or death within 15, 30, and 180 days of COVID-19 diagnosis. Use of N-BP was defined as a prescription within 3 years prior. ICU admission and ventilator use were determined using administrative codes. Death included both in-hospital and out-of-hospital events. Patients treated with N-BP were matched 1:1 by propensity score to patients without prior N-BP use. Secondary analysis compared outcomes among those prescribed zoledronic acid (ZOL) to those prescribed oral N-BPs. RESULTS: Of 76,223 COVID-19 patients identified, 1,853 were previously prescribed N-BP, among whom 559 were prescribed ZOL. After propensity score matching, there were no significant differences in the composite outcome at 15 days (HR 1.22, 95% CI: 0.89-1.67), 30 days (HR 1.24, 95% CI: 0.93-1.66), or 180 days (HR 1.17, 95% CI: 0.93-1.48), comparing those prescribed and not prescribed N-BP. Compared to those prescribed oral N-BP, there were no significant differences in outcomes among those prescribed ZOL. CONCLUSION: Among older COVID-19 patients, prior exposure to N-BP including ZOL was not associated with a reduction in ICU admission, ventilator use, or death.

Intra-articular injection of human mesenchymal stem cells (MSCs) promote rat meniscal regeneration by being activated to express Indian hedgehog that enhances expression of type II collagen.

OBJECTIVE: Meniscal regeneration was previously shown to be enhanced by injection of mesenchymal stem/stromal cells (MSCs) but the mode of action of the MSCs was not established. The aim of this study was to define how injection of MSCs enhances meniscal regeneration. DESIGN: A hemi-meniscectomy model in rats was used. Rat-MSCs (rMSCs) or human-MSCs (hMSCs) were injected into the right knee joint after the surgery, and PBS was injected into the left. The groups were compared macroscopically and histologically at 2, 4, and 8 weeks. The changes in transcription in both human and rat genes were assayed by species-specific microarrays and real-time RT-PCRs. RESULTS: Although the number of hMSCs decreased with time, hMSCs enhanced meniscal regeneration in a manner similar to rMSCs. hMSCs injection increased expression of rat type II collagen (rat-Col II), and inhibited osteoarthritis progression. The small fraction of hMSCs was activated to express high levels of a series of genes including Indian hedgehog (Ihh), parathyroid hormone-like hormone (PTHLH), and bone morphogenetic protein 2 (BMP2). The presence of hMSCs triggered the subsequent expression of rat-Col II. An antagonist of hedgehog signaling inhibited the expression of rat-Col II and an agonist increased expression of rat-Col II in the absence of hMSCs. CONCLUSIONS: Despite rapid reduction in cell numbers, intra-articular injected hMSCs were activated to express Ihh, PTHLH, and BMP2 and contributed to meniscal regeneration. The hedgehog signaling was essential in enhancing the expression of rat-Col II, but several other factors provided by the hMSCs probably contributed to the repair.

At-home determination of 24-h urine sodium excretion: Validation of chloride test strips and multiple spot samples.

Sodium intake and compliance with dietary sodium modification are typically assessed using a 24-h urine collection analyzed using flame photometry, but this is inconvenient. Spot urine samples have been investigated as alternatives to 24-h collections, but their accuracy is poor. Since sodium and chloride are present in equal concentrations in dietary salt, chloride test strips may provide a suitable proxy for at-home measurement of urine sodium concentrations. We aimed to determine whether (i) chloride test strips provide a reliable measure of urinary sodium compared to the gold standard flame photometry and (ii) multiple spot samples accurately reflect 24-h urine sodium. We recruited 43 participants (19 males) aged 23.6 ± 0.6 years to complete multiple consecutive spot samples (morning and evening) along with a 24-h urine sodium collection. Urine 24-h sodium estimates using chloride test strips (114.6 ± 7.5 mmol/day) were highly correlated (r = 0.900, p < 0.0001) with flame photometry (121.1 ± 7.7 mmol/day) with a bias of -6.53 ± 22.2 mmol/day. Use of a three-spot sample average (both morning and evening spot samples) with a correction factor applied (122.9 ± 4.1 mmol/day) provided a good approximation of 24-h sodium measured by flame photometry (125.6 ± 9.0 mmol/day), with a bias of -2.55 ± 43.9 mmol/day. Chloride test strips applied to a 24-h urine collection provide a highly accurate measure of urinary sodium excretion, permitting convenient at-home sample collection and analysis. Their application to multiple spot samples provides a reasonable approximation of sodium excretion that can be used to conveniently monitor attempts at dietary sodium manipulation, without the inconvenience of completing a 24-h urine sample.

Oocyte maturation in starfish is mediated by the beta gamma-subunit complex of a G-protein.

The stimulation of meiotic maturation of starfish oocytes by the hormone 1-methyladenine is mimicked by injection of beta gamma subunits of G-proteins from either retina or brain. Conversely, the hormone response is inhibited by injection of the GDP-bound forms of alpha i1 or alpha t subunits, or by injection of phosducin; all of these proteins should bind free beta gamma. alpha-subunit forms with reduced affinity for beta gamma (alpha i1 or alpha t bound to hydrolysis-resistant GTP analogs, or alpha i1-GMPPCP treated with trypsin to remove the amino terminus of the protein) are less effective inhibitors of 1-methyladenine action. These results indicate that the beta gamma subunit of a G-protein mediates 1-methyladenine stimulation of oocyte maturation.

Hydrophobicity of amino acid residues in globular proteins.

During biosynthesis, a globular protein folds into a tight particle with an interior core that is shielded from the surrounding solvent. The hydrophobic effect is thought to play a key role in mediating this process: nonpolar residues expelled from water engender a molecular interior where they can be buried. Paradoxically, results of earlier quantitative analyses have suggested that the tendency for nonpolar residues to be buried within proteins is weak. However, such analyses merely classify residues as either "exposed" or "buried." In the experiment reported in this article proteins of known structure were used to measure the average area that each residue buries upon folding. This characteristic quantity, the average area buried, is correlated with residue hydrophobicity.

Human albumin preserves islet mass and function better than whole serum during pretransplantation islet culture.

OBJECTIVE: Human islet transplant protocols frequently include a brief period of islet culture before transplantation. Some investigators have suggested that medium supplementation with human serum might quench collagenase activity and provide better culture conditions when compared with human albumin. We studied the effect of whole serum on islet count, islet equivalence, insulin secretion, and DNA content in human islets. METHODS: Adult human islets isolated from a single pancreas with purity >50% were cultured in identical 150 islet equivalent samples at 37 degrees C using CMRL 1066-based islet medium (Mediatech) supplemented with either 0.5% human albumin or 10% human AB serum. Prior to culture and after 3 days, islets were assessed in vitro using dithizone staining (n = 4), insulin release after static glucose stimulation (n = 8), and DNA content (n = 8). RESULTS: After 3 days, islet mass (defined by the number of islets and islet equivalents counted after dithizone staining) was better preserved in islets cultured in 0.5% human albumin. Although the stimulation index and total DNA content were similar between groups, islets cultured in human albumin demonstrated greater absolute insulin secretion (p = .02) and insulin secretion per cell (p = .02). CONCLUSIONS: When used to supplement CMRL 1066-based islet culture medium, human albumin preserves islet mass and secretory capacity better than whole human serum. Human serum offers no advantage in islet preservation or function.

Snf1 kinase connects nutritional pathways controlling meiosis in Saccharomyces cerevisiae.

Glucose inhibits meiosis in Saccharomyces cerevisiae at three different steps (IME1 transcription, IME2 transcription, and entry into late stages of meiosis). Because many of the regulatory effects of glucose in yeast are mediated through the inhibition of Snf1 kinase, a component of the glucose repression pathway, we determined the role of SNF1 in regulating meiosis. Deleting SNF1 repressed meiosis at the same three steps that were inhibited by glucose, suggesting that glucose blocks meiosis by inhibiting Snf1. For example, the snf1Delta mutant completely failed to induce IME1 transcripts in sporulation medium. Furthermore, even when this block was bypassed by expression of IME1 from a multicopy plasmid, IME2 transcription and meiotic initiation occurred at only 10 to 20% of the levels seen in wild-type cells. The addition of glucose did not further inhibit IME2 transcription, suggesting that Snf1 is the primary mediator of glucose controls on IME2 expression. Finally, in snf1Delta cells in which both blocks on meiotic initiation were bypassed, early stages of meiosis (DNA replication and commitment to recombination) occurred, but later stages (chromosome segregation and spore formation) did not, suggesting that Snf1 controls later stages of meiosis independently from the two controls on meiotic initiation. Because Snf1 is known to activate the expression of genes required for acetate metabolism, it may also serve to connect glucose and acetate controls on meiotic differentiation.

Nutritional regulation of late meiotic events in Saccharomyces cerevisiae through a pathway distinct from initiation.

The IME1 gene is essential for initiation of meiosis in the yeast Saccharomyces cerevisiae, although it is not required for growth. Here we report that in stationary-phase cultures containing low concentration of glucose, cells overexpressing IME1 undergo the early meiotic events, including DNA replication, commitment to recombination, and synaptonemal complex formation and dissolution. In contrast, later meiotic events, such as chromosome segregation, commitment to meiosis, and spore formation, do not occur. Thus, nutrients can repress the late stages of meiosis independently of their block of initiation. Cells arrested at this midpoint in meiosis are relatively stable and can resume meiotic differentiation if transferred to sporulation conditions. Resumption of meiosis does not require repression of IME1 expression, since IME1 RNA levels stay high after transfer of the arrested cells to sporulation medium. These results suggest that meiosis in S. cerevisiae is a paradigm of a differentiation pathway regulated by signal transduction at both early and late stages.

Erratum: iPS-derived MSCs from an expandable bank to deliver a prodrug-converting enzyme that limits growth and metastases of human breast cancers.

[This corrects the article DOI: 10.1038/cddiscovery.2016.64.].

iPS-derived MSCs from an expandable bank to deliver a prodrug-converting enzyme that limits growth and metastases of human breast cancers.

One attractive strategy to treat cancers is to deliver an exogenous enzyme that will convert a non-toxic compound to a highly toxic derivative. The strategy was tested with viral vectors but was disappointing because the efficiency of transduction into tumor cells was too low. Recent reports demonstrated that the limitation can be addressed by using tissue-derived mesenchymal stromal cells (MSCs) to deliver enzyme/prodrug systems that kill adjacent cancer cells through bystander effects. Here we addressed the limitation that tissue-derived MSCs vary in their properties and are difficult to generate in the large numbers needed for clinical applications. We prepared a Feeder Stock of MSCs from induced pluripotent stem cells (iPSs) that provided an extensively expandable source of standardized cells. We then transduced the iPS-derived MSCs to express cytosine deaminase and injected them locally into a mouse xenogeneic model of human breast cancer. After administration of the prodrug (5-fluorocytosine), the transduced iPS-MSCs both limited growth of preformed tumors and decreased lung metastases.

The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population.

OBJECTIVE: To establish the prevalence of intrahepatic cholestasis of pregnancy (ICP) in a primarily Latina population in the United States. STUDY DESIGN: Over a period of 16 months, a convenience sample of subjects admitted to labor and delivery in the third trimester was enrolled. Each subject completed a questionnaire rating their severity of pruritus on a numeric scale of 1 to 10. Serum was analyzed via radioimmunoassay for total bile acid concentration. ICP was defined as pruritus score >4 and a total serum bile acid concentration of >or=20 micromol/l. Ethnicity was determined from hospital record demographic data. RESULTS: All invited participants enrolled in the study. Three hundred and forty subjects were enrolled. Three hundred and sixteen subjects (93%) were identified as Latina. The serum bile acid concentration range for the entire study population was 1 to 580 micromol/l with a mean of 10.4+/-34.9 micromol/l. Twenty-four (7.1%) subjects had a serum bile acid concentration >or=20 micromol/l. A pruritus score >4 was found in 19.7% (67/340). Of the 24 subjects with a bile acid concentration >or=20 micromol/l, 19 also had a pruritus score >4. Thus, the prevalence of ICP in this population was 5.6% (19/340). In subjects with ICP, the mean serum bile acid concentration was 89.5+/-124.0 micromol/l. When controlling for confounders, women with ICP were associated with higher rates of chorioamnionitis (P=0.043) and their fetuses had higher rates of thick meconium (P=0.053). CONCLUSIONS: The overall prevalence of ICP in this population was 5.6%, 10 to 100 times higher than previously reported data from the United States. Larger studies of perinatal morbidity examining the diagnostic criteria of cholestasis need to be conducted.

Platelet immunoreceptor tyrosine-based activation motif (ITAM) and hemITAM signaling and vascular integrity in inflammation and development.

Platelets are essential for maintaining hemostasis following mechanical injury to the vasculature. Besides this established function, novel roles of platelets are becoming increasingly recognized, which are critical in non-injury settings to maintain vascular barrier integrity. For example, during embryogenesis platelets act to support the proper separation of blood and lymphatic vessels. This role continues beyond birth, where platelets prevent leakage of blood into the lymphatic vessel network. During the course of inflammation, platelets are necessary to prevent local hemorrhage due to neutrophil diapedesis and disruption of endothelial cell-cell junctions. Surprisingly, platelets also work to secure tumor-associated blood vessels, inhibiting excessive vessel permeability and intra-tumor hemorrhaging. Interestingly, many of these novel platelet functions depend on immunoreceptor tyrosine-based activation motif (ITAM) signaling but not on signaling via G protein-coupled receptors, which plays a crucial role in platelet plug formation at sites of mechanical injury. Murine platelets express two ITAM-containing receptors: the Fc receptor γ-chain (FcRγ), which functionally associates with the collagen receptor GPVI, and the C-type lectin-like 2 (CLEC-2) receptor, a hemITAM receptor for the mucin-type glycoprotein podoplanin. Human platelets express an additional ITAM receptor, FcγRIIA. These receptors share common downstream effectors, including Syk, SLP-76 and PLCγ2. Here we will review the recent literature that highlights a critical role for platelet GPVI/FcRγ and CLEC-2 in vascular integrity during development and inflammation in mice and discuss the relevance to human disease.

Activated human mesenchymal stem/stromal cells suppress metastatic features of MDA-MB-231 cells by secreting IFN-ß.

Our recent study showed that human mesenchymal stem/stromal cells (hMSCs) are activated to express tumor necrosis factor (TNF)-α-related apoptosis-inducing ligand (TRAIL) by exposure to TNF-α and these activated hMSCs effectively induce apoptosis in triple-negative breast cancer MDA-MB-231 (MDA) cells in vitro and in vivo. Here, we further demonstrated that activated hMSCs not only induced apoptosis of MDA cells but also reduced metastatic features in MDA cells. These activated hMSC-exposed MDA cells showed reduced tumorigenicity and suppressed formation of lung metastasis when implanted in the mammary fat pad. Surprisingly, the activated hMSC-exposed MDA cells increased TRAIL expression, resulting in apoptosis in MDA cells. Interestingly, upregulation of TRAIL in MDA cells was mediated by interferon-beta (IFN-ß) secreted from activated hMSCs. Furthermore, IFN-ß in activated hMSCs was induced by RNA and DNA released from apoptotic MDA cells in absent in melanoma 2 (AIM2) and IFN induced with helicase C domain 1 (IFIH1)-dependent manners. These observations were only seen in the TRAIL-sensitive breast cancer cell lines but not in the TRAIL-resistant breast cancer cell lines. Consistent with these results, Kaplan-Meier survival analysis also showed that lack of innate sensors detecting DNA or RNA is strongly associated with poor survival in estrogen receptor-negative breast cancer patients. In addition, cancer-associated fibroblasts (CAF) isolated from a breast cancer patient were also able to express TRAIL and IFN-ß upon DNA and RNA stimulation. Therefore, our results suggest that the crosstalk between TRAIL-sensitive cancer cells and stromal cells creates a tumor-suppressive microenvironment and further provide a novel therapeutic approach to target stromal cells within cancer microenvironment for TRAIL sensitive cancer treatment.

Weight management for adolescents with intellectual and developmental disabilities: Rationale and design for an 18month randomized trial.

Adolescents with intellectual and developmental disabilities (IDD) are an underserved group in need of weight management. However, information regarding effective weight management for this group is limited, and is based primarily on results from small, non-powered, non-randomized trials that were not conducted in accordance with current weight management guidelines. Additionally, the comparative effectiveness of emerging dietary approaches, such as portion-controlled meals (PCMs) or program delivery strategies such as video chat using tablet computers have not been evaluated. Therefore, we will conduct an 18month trial to compare weight loss (6months) and maintenance (7-18months) in 123 overweight/obese adolescents with mild to moderate IDD, and a parent, randomized to a weight management intervention delivered remotely using FaceTime™ on an iPad using either a conventional meal plan diet (RD/CD) or a Stop Light diet enhanced with PCMs (RD/eSLD), or conventional diet delivered during face-to-face home visits (FTF/CD). This design will provide an adequately powered comparison of both diet (CD vs. eSLD) and delivery strategy (FTF vs. RD). Exploratory analyses will examine the influence of behavioral session attendance, compliance with recommendations for diet (energy intake), physical activity (min/day), self-monitoring of diet and physical activity, medications, and parental variables including diet quality, physical activity, baseline weight, weight change, and beliefs and attitudes regarding diet and physical activity on both weight loss and maintenance. We will also complete a cost and contingent valuation analysis to compare costs between RD and FTF delivery.

Labor induction utilizing the Foley balloon: a randomized trial comparing standard placement versus immediate removal.

OBJECTIVE: To compare time to delivery between two induction procedures. The Foley balloon is a mechanical method for cervical ripening. However, the device may also result in endogenous prostaglandin release following separation of the chorionic membrane and decidua. Prolonged Foley placement may therefore be unnecessary for successful labor induction. METHOD: Randomized controlled trial of labor induction at LAC+USC Medical Center between 2010 and 2013. Subjects were assigned to either (a) standard placement of the Foley balloon or (b) Foley balloon insufflation and immediate removal. Oxytocin was administered to all subjects not in active labor after 12 h. Delivery information and neonatal outcomes were documented and all patients were followed for 6 weeks for adverse events. RESULT: A total of 79 women were included in the analysis (37 standard and 42 immediate). Induction time was 8.6 h longer in the immediate removal group (23.5 vs 32.1, P=0.002), but the difference in delivery within 24 h did not meet the statistical significance (46.0 vs 28.6%, P=0.11). Similar rates of cesarean delivery, epidural use and abnormal APGAR scores were observed. After controlling for number of vaginal exams and duration of rupture, a decreased risk of infection was observed in the immediate removal group (odds ratio=0.08, 95% confidence interval=0.007 to 0.93, P=0.04). Further, when the analysis was stratified by parity, differences in induction time only persisted in nulliparous women. CONCLUSION: Immediate removal of the Foley balloon may lead to longer overall induction time, but a lower risk of infection. Parous women may be particularly good candidates for this type of induction.

Impact of adjuvant chemotherapy on cosmesis and complications in stages I and II carcinoma of the breast treated by biopsy and radiation therapy.

Cosmesis and complication rates were examined in patients with early stage carcinoma of the breast treated by biopsy and radiation therapy with and without adjuvant chemotherapy in an attempt to determine the effect of chemotherapy upon these parameters. Between April 1, 1975 and June 1, 1980, 51 patients were treated with radiation therapy and adjuvant chemotherapy (XRT + ACT) and 83 patients with radiotherapy alone (XRT). Chemotherapy usually consisted of cytoxan, methotrexate and 5-fluorouracil for 6 or 12 cycles. Minimum follow-up was 36 months. Cosmetic results deteriorated with time in both groups but to a greater extent in the XRT + ACT group. At 36 months, excellent cosmetic results were obtained in 73 of the 83 patients (88%) in the XRT group compared to 37 of 51 patients (73%) in the XRT + ACT group (p = less than .05). Comparison of the two treatment groups revealed that complication rates were significantly increased in the XRT + ACT group. Of the 51 patients in the XRT + ACT group, 21 patients (41%) suffered complications compared to 8 (10%) of the 83 patients in the XRT group (p = less than .001). This difference in complication rates resulted primarily from an increased incidence in the XRT + ACT group of wet desquamation in the electron beam portal used to treat the internal mammary lymph nodes and a trend towards a higher incidence of spontaneous nonpathologic rib fractures, myositis and arm edema. An increased incidence of nonbreast primary cancers was not seen. Our preliminary conclusions are that adjuvant chemotherapy has a negative impact upon cosmesis and complication rates in patients being treated with definitive radiotherapy. However, cosmetic results remain satisfactory and complication rates are maintained at an acceptable level. Continued close follow-up will be required before definitive conclusions can be reached as to the overall incidence and severity of the changes noted.

Biopsy and definitive radiation therapy in stages I and II carcinoma of the female breast.

One hundred-twenty patients with Stages I and II carcinoma of the female breast were treated by biopsy followed by definitive radiation therapy without mastectomy. The breast received 4500-5000 cGy (rad) using a 6 MV linear accelerator followed by a supplement to the area of the primary tumor of 2000 cGy (rad) using electrons in 99 patients (83%) and interstitial implantation in 21 patients (17%). Local recurrence was not recorded in the 43 patients with Stage I disease, while three of 77 patients (4%) with Stage II disease suffered a local recurrence. The actuarial five-year relapse-free survival was 91% and 60% in Stages I and II respectively. Cosmetic results were considered excellent by both physician and patient in the majority of cases. Axillary dissection was the recommended method of staging the axilla but was noted to be more morbid than axillary sampling. Electrons may be as effective as interstitial implantation as a means of supplementation following external beam therapy if specific guidelines are followed.

Rod photoreceptor cells dissociated from mature mice retinas.

Intact rod photoreceptors were dissociated from pronase-treated whole retinas of adult mice by repeated passage through a plastic pipette tip. Hemocytometer counts of the cell suspensions indicate that, during a series of ten dissociation steps, a total of about 1-2 million intact photoreceptor cells are dissociated from one adult mouse retina, with less than 5% contamination from Müller cells and neurons of the inner retina. Visual cells with rod outer segments (ROS) and synaptic terminals are released in each step, but they occur in the greatest number during the sixth to ninth steps; detached ROS are released most frequently in the early steps, and neurons of the inner retinal layers appear in the later steps of dissociation. Nuclei are found in each step. Cell intactness was estimated by Trypan blue and Erythrosin B exclusion and by microscopic analysis using differential interference optics or scanning electron microscopy. The cells bind lectins (concanavalin A, Ricinis communis, and wheat germ agglutinin but not peanut agglutinin), displaying surface topography like that observed in situ. The metabolic capacity of dissociated cells was assessed by measuring the utilization of 32P inorganic phosphate for the synthesis of phospholipids and for the light-dependent phosphorylation of rhodopsin. Mature photoreceptor cells were estimated to contain, on average, 6.4 X 10(-12) g DNA, 2.3 X 10(-12) g RNA and 42-64 X 10(-12) g protein. The dissociation procedure provides a population of photoreceptor cells that appears suitable for microscopic, electrophysiological, and biochemical analysis.

Phosphodiesterase-probes show distinct defects in rd mice and Irish setter dog disorders.

The phosphodiesterase from the visual cells of rd mice and affected Irish setter dogs has been analyzed, using biochemical, biophysical, and immunological techniques. The authors' findings demonstrate that the mechanisms that cause a deficiency in phosphodiesterase activity in rd mice and Irish setter dogs are distinctly different. Apparently, the phosphodiesterase complex is normal in affected Irish setter dogs but is abnormal in rd mice. The criteria used for determining the normalcy of the phosphodiesterase complex were sedimentation characteristics, immuno-cross-reactivity, and histone-activation, which is shown to be a unique characteristic of the visual cell enzyme. According to these criteria, the phosphodiesterase complex in the visual cells of rd mice is either absent or abnormal from the onset of visual cell differentiation until degeneration, because it exhibits no cross-reactivity with antibody to phosphodiesterase; it is not activated by histone; and if present, it exhibits abnormal sedimentation characteristics and perhaps subunit structure. On the other hand, phosphodiesterase from the visual cells of affected Irish setter dogs is normal by the same criteria, because it cross-reacts with antibody against phosphodiesterase; it is activated by histone; and it exhibits normal sedimentation and electrophoretic patterns. It is proposed that depressed levels of phosphodiesterase activity in affected setter photoreceptors are due, perhaps, to a defect in the light-initiated cascade which activates the enzyme normally, in situ.