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Tarakan City has several road segments on provincial roads that have experienced significant damage in the form of sinkholes and substantial potholes on the road surface. These deteriorations are primarily attributed to the impact of traffic, excessive traffic loads, subgrade soil conditions that fall short of requirements, and the use of pavement materials that do not meet the specified standards. To devise effective road repair plans, the collection of field data is crucial. Two distinct methods are employed for data collection to assess pavement conditions: the International Roughness Index (IRI) and the Surface Distress Index (SDI). The IRI method measures road roughness using the Rough meter III instrument, while the SDI method focuses on parameters like crack area, crack width, pothole count, and wheel path rut depth. The surveyed road sections encompass Amal Lama, Gunung Selatan, Aji Iskandar, Bhayangkara, Aki Pingka, and the Ring Road of Tarakan City. Research findings reveal the surface damage level of roads in Tarakan City using the SDI and IRI methods, with the following breakdown: roads in good condition account for 42.86%, those in moderate condition make up 51.90%, slightly damaged roads constitute 4.8%, and heavily damaged roads represent 0.44%. Additionally, the study has determined the percentage of each type of maintenance required: Routine Maintenance at 94.77%, Periodic Maintenance at 4.8%, and Reconstruction at 0.44%.

A patient with well-differentiated thyroid carcinoma had a whole body scan using 5 mCi I which demonstrated abnormal uptake of I in a palpable pelvic mass. Approximately 24 years ago the patient had a total thyroidectomy followed by I treatment. The histologic examination of the mass was consistent with serous cystadenoma of the ovary. No thyroid tissue or teratoma was identified. The mechanism for the unusual uptake of I in a benign ovarian tumor is not clear, and the differential diagnosis of metastatic thyroid cancer is briefly reviewed. [ABSTRACT FROM AUTHOR]

A key aspect that must be supervised during the development of recombinant therapeutic products is the potential presence of impurities. Residual host cell proteins (HCPs) are a major class of process-related impurities derived from the host organism that even in trace amount have the potential to affect product quality, safety, and efficacy. Therefore, the product purification processes must be optimized to consistently remove as many HCPs as feasible, with the goal of making the product as pure as possible. The workhorse of HCP monitoring and quantitation during bioprocessing manufacturing is sandwich ELISA (enzyme-linked immunosorbent assay), which employs polyclonal anti-HCP antibodies for both capture and detection. Commercial ELISA kits developed from Chinese Hamster Ovary (CHO) cell lines are widely applied in early drug development stages (preclinical, phase I, and phase II), but are not specifically designed for a given manufacturer's proprietary cell line, and users do not have control over reagent availability and lot-to-lot consistency. For later development stages, the upstream process-specific method is preferred to guarantee an improved sensitivity and coverage. In agreement with the USP General Chapter 〈1132〉, a platform assay can be used in place of the commercial one through all stages of product development, if already available when product development starts. This proof-of-concept study was carried out to demonstrate the feasibility and the advantages of the development of a proprietary CHO HCPs platform ELISA. Different proprietary mock materials have been characterized and compared by orthogonal bidimensional electrophoresis techniques (SDS-PAGE coupled to SS/WB and 2D DIGE) with the scope of selecting the best antigen-antibody couple for setting up the in-house ELISA. A preliminary evaluation of the in-house method performance has been done in comparison with the commercial assay, demonstrating that the platform method is promising for an accurate and precise CHO HCPs quantification during the early phase product and process development., Competing Interests: Declaration of Competing Interest The authors have read the journal's policy and have the following competing interests: Elisa Giordano, Irene Cecchini, Roberta Verani, Lidia Leone and Barbara Liori were paid employees of Merck Serono S.p.A., an affiliate of Merck KgaA, Darmstadt, Germany at the date of the experiments. This research was performed using products under development by Merck KGaA. While Merck KGaA has filed for patent protection regarding the products under development, the technologies described in this manuscript are independent from Merck KGaA products. This does not alter our adherence to the journal policies on sharing data and materials. No patents or patent applications have been filed for the technologies described in this manuscript., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Homozygous deficiencies of early components for complement activation are among the strongest genetic risk factors for human systemic lupus erythematosus (SLE). Eleven cases of C1r deficiency are documented but this is the first report on the molecular basis of C1r deficiency. The proband is an African-American male who developed SLE at 3 months of age. He had a discoid lupus rash and diffuse proliferative glomerulonephritis. Serum complement analysis of the patient showed zero CH50 activity, undetectable C1r, and reduced levels of C1s, but highly elevated levels of complement C4, C2, and C1-inhibitor. The coding regions of the mutant C1R gene with 11 exons located at chromosome 12p13 were polymerase chain reaction (PCR)-amplified and sequenced to completion. DNA sequencing revealed a homozygous C→T mutation at nucleotide-6392 in exon 10 of the C1R gene, resulting in a nonsense mutation from Arg-380 (R380X). The patient's clinically normal mother was heterozygous for this mutation. A sequence-specific primer (SSP) PCR coupled with StuI-restriction fragment length polymorphism (RFLP) was developed to detect the novel mutation. Screening of 209 African-American SLE patients suggested that the R380X mutation is a rare causal variant. Mutations leading to early complement component deficiencies in SLE are mostly private variants with large effects.

The mGlu5 receptor is the only metabotropic glutamate receptor subtype expressed by mouse embryonic stem (ES) cells grown under non-differentiating conditions [Cappuccio, I., Spinanti, P. Porcellini, A., Desiderati, F., De Vita, T., Storto, M., Capobianco, L., Battaglia, G., Nicoletti, F., Melchiorri, D., 2005. Endogenous activation of mGlu5 metabotropic glutamate receptors supports self-renewal of cultured mouse embryonic stem cells. Neuropharmacology 1, 196-205]. We now report that ES cells differentiating into embryoid bodies (EBs) progressively lose mGlu5 receptors and begin to express mGlu4 receptors at both mRNA and proteinc level. A 4-day treatment of EBs with the mGlu4 receptor agonist, L-2-amino-4-phosphonobutanoate (L-AP4), increased mRNA levels of the mesoderm marker, brachyury and the endoderm marker, H19, and decreased the expression of the transcript for the primitive ectoderm marker, fibroblast-growth factor-5 (FGF-5). These effects were prevented by the mGlu4 receptor antagonists, alpha-methylserine-O-phosphate (MSOP). Plating of EBs for 4 days in vitro in ITSFn medium induced cell differentiation towards a neural lineage, as reflected by the expression of the intermediate filament protein, nestin, and the homeobox protein, Dlx-2. Pharmacological activation of mGlu4 receptors during cell incubation in ITSFn medium increased the expression of both neural markers. Similar results were obtained when neural differentiation was induced by exposure of EBs to retinoic acid. These data suggest that differentiation of cultured ES cells is associated with changes in the expression pattern of mGlu receptors and that activation of mGlu4 receptors affects cell differentiation in a context-dependent manner.

Background: The addition of phosphorothioate (PS) groups to natural phosphodiester (PD) antisense oligodeoxynucleotides (oligo) prevents their in vivo hydrolysis by nucleases allowing an RNase-dependent elimination of targeted mRNA. To further improve oligo function 2'-methoxyethyl (ME) groups were attached to selected nucleotides at the 3'-end because ME groups block RNase activity., Methods/results: ME modification of PS- or PD/PS-oligo targeting human intracellular adhesion molecule (ICAM)-1 mRNA significantly increased the degree and duration of the in vitro inhibitory effects without compromising selectivity and specificity. A 7-day intravenous or oral therapy with rat ME/PS-modified ICAM-1 antisense oligo extended the survivals of kidney allografts. In addition, ME/PS-modified ICAM-1 antisense oligo reduced ischemic-reperfusion injury in kidneys, as measured by glomerular filtration rate, creatinine levels, and infiltration with leukocytes. Finally, a 14-day treatment with cyclosporine (CsA)-induced nephrotoxicity in syngeneic kidney transplants correlated with both increased ICAM-1 protein expression and infiltration with leukocytes. Graft perfusion and treatment of recipients with ICAM-1 antisense ME/PS-oligo alleviated the nephrotoxic effect and decreased ICAM-1 expression and leukocyte infiltration., Conclusions: ME/PS-modified ICAM-1 antisense oligo is very effective in inhibiting the ICAM-1-dependent mechanism of graft infiltration and tissue damage involved in allograft rejection, ischemic-reperfusion injury, and CsA-induced nephrotoxicity.

The cytoplasmic localized Janus tyrosine kinase 3 (Jak3) is activated by multiple cytokines, including IL-2, IL-4, and IL-7, through engagement of the IL-2R common gamma-chain. Genetic inactivation of Jak3 is manifested as SCID in humans and mice. These findings have suggested that Jak3 represents a pharmacological target to control certain lymphoid-derived diseases. Using the rat T cell line Nb2-11c, we document that tyrphostin AG-490 blocked in vitro IL-2-induced cell proliferation (IC(50) approximately 20 microM), Jak3 autophosphorylation, and activation of its key substrates, Stat5a and Stat5b, as measured by tyrosine/serine phosphorylation analysis and DNA-binding experiments. To test the notion that inhibition of Jak3 provides immunosuppressive potential, a 7-day course of i.v. therapy with 5-20 mg/kg AG-490 was used to inhibit rejection of heterotopically transplanted Lewis (RT1(l)) heart allografts in ACI (RT1(a)) recipients. In this study, we report that AG-490 significantly prolonged allograft survival, but also acted synergistically when used in combination with the signal 1 inhibitor cyclosporin A, but not the signal 3 inhibitor, rapamycin. Finally, AG-490 treatment reduced graft infiltration of mononuclear cells and Stat5a/b DNA binding of ex vivo IL-2-stimulated graft infiltrating of mononuclear cells, but failed to affect IL2R alpha expression, as judged by RNase protection assays. Thus, inhibition of Jak3 prolongs allograft survival and also potentiates the immunosuppressive effects of cyclosporin A, but not rapamycin.

Background: It is widely accepted that minimal change nephrotic syndrome (MCNS) is the most common cause of nephrosis in children. Recent studies have demonstrated an increasing incidence of focal segmental glomerulosclerosis (FSGS) in adults., Methods: To determine possible changes in the etiology of childhood nephrosis, the clinical charts of 152 pediatric patients diagnosed with idiopathic nephrotic syndrome between 1978 and 1997 were reviewed. Histopathological diagnosis was available in 105 patients., Results: MCNS was present in 35% of all biopsies, whereas FSGS was observed in 31%. Even if we assume that all patients without a histological diagnosis had MCNS (presumptive MCNS), the total incidence of MCNS (biopsy proven + presumptive) in our population was only 55%. We observed a dramatic increase in the incidence of FSGS during recent years. Before 1990, FSGS was diagnosed in 23% of all renal biopsies but increased to 47% afterward (P = 0.02). This pattern was observed in all ethnic groups. In African Americans, there was a trend for an increase in the incidence of FSGS from 38% before 1990 to 69% after 1990. A similar trend was observed in Caucasians (from 20 to 45%) and Hispanics (from 8 to 33%) Hispanics had the highest incidence of MCNS (biopsy proven + presumptive: 73%), followed by Caucasians (53%) and African Americans (37%). The mean age for presentation of nephrotic syndrome in African Americans (8.0 +/- 0.9 years) was higher than in Caucasians (4.1 +/- 0.05) and Hispanics (3.3 +/- 0.5)., Conclusions: Our study showed that the incidence of FSGS in children with idiopathic nephrotic syndrome has increased recently. Furthermore, in African American children. FSGS is the most common cause of nephrotic syndrome. These findings may have significant implications in the management of childhood nephrotic syndrome.

Renal cell carcinoma (RCC) arising in acquired cystic kidney disease (ACKD) is considered to be a tumor of low malignant potential, compared with classic RCC. The aim of the present study was to identify any significant differences in the antigenic profiles or tumor cell proliferative activity of ACKD-associated RCC and classic RCC that might be responsible for differences in their biologic behavior. We studied the immunohistochemical profiles and proliferative activity of 12 classic RCCs and 5 ACKD-associated RCCs with markers of proximal tubules (Leu M1, alpha-1 antitrypsin, CAM 5.2), markers of distal tubules (Arachis hypogaea lectin, AE1/AE3, epithelial membrane antigen [EMAJ, CAM 5.2), vimentin, and proliferating cell nuclear antigen (PCNA). We performed proliferation analysis with the CAS 200 image analysis system. For each case, 8 to 20 fields of tumor tissue in the areas of maximal PCNA staining were quantitated, and the percentage of PCNA-positive nuclear area for each individual tumor was calculated. All of the five ACKD-associated RCCs expressed AE1/AE3, EMA, and CAM 5.2 in more than 50% of the tumor cells. Arachis hypogaea lectin was significantly expressed in three of the five ACKD-associated RCCs. Leu M1 and alpha-1 antitrypsin reacted with fewer than 10% of the tumor cells in all of the five ACKD-associated RCCs. In contrast, the 12 classic RCCs showed expression of CAM 5.2 in 11 cases, alpha-1 antitrypsin in 10 cases, Leu M1 in 9, EMA in 8, and AE1/AE3 in 3 cases in more than 50% of the tumor cells and a totally negative reaction with Arachis hypogaea lectin in 8 cases, EMA in 4, AE1/AE3 in 4, and vimentin in 5 cases. Although coexpression of proximal and distal tubule markers was seen in some cases of RCC in either category, there was uniform and strong staining for distal tubule markers in ACKD-associated RCC and for proximal tubule markers in classic RCC. The mean percentage of PCNA-positive nuclear area for the ACKD-associated RCCs (2.41%) was significantly (P < .05) less than that of the classic RCCs (21.42%). The differences in expression of proximal and distal tubule markers and proliferative activity might be responsible for the differences in the biologic behavior of ACKD-associated RCC and classic RCC.

The single dose administration of the aminonucleoside of puromycin (PAN) induces a nephrotic syndrome in rats characterized by massive proteinuria and progressive histologic changes. This model of acute parenchymal nephritis is thought to be mediated by the renal recruitment of monocytes and macrophages. To investigate the role of leukocytes in the experimental nephrotic syndrome model, the effects of two methylxanthines, pentoxifylline (45 mg/kg i.p. twice daily) and torbafylline (5 mg/kg i.p. twice daily) were compared with controls over a 2-week period. Pentoxifylline treatment was associated with 3- and 6-fold reductions in urinary protein excretion at 7 and 14 days, respectively, compared with PAN-treated control animals (p < .01). Similarly, 14-day dosing of torbafylline resulted in a 3-fold decrease in urinary protein excretion. Glomerular filtration and electrolyte excretion rates were similar between all treatment groups. There were significant reductions in glomerular neutrophil and macro-phage counts, but not T-cells (OX19+) or suppressor/cytotoxic T-cells (0X8+), in kidneys of rats given either treatment compared with PAN con-trol rats. In summary, both pentoxifylline and torbafylline attenuated the proteinuria and glomerular macrophage and neutrophil infiltration associated with PAN administration. These data support the role of macrophages and neutrophils in the pathogenesis of acute parenchymal injury and the potential role of pentoxifylline or related analogues in the attenuation of the ensuing renal deficit associated with minimal lesion disease.

Tenascin, a large oligomeric glycoprotein, is a recent addition to a list of increasing extracellular matrix proteins. Previous studies have documented the strong expression of tenascin in embryonic kidney and in both normal and abnormal mature glomeruli implicating an important role of this extracellular matrix protein in nephrogenesis and glomerular scarring. Whether tenascin plays any role in interstitial fibrosis, a common final pathway of tubulointerstitial nephritis, is no known; on the other hand, a detailed knowledge of the structural components of interstitial fibrosis is essential for further studies on other fundamental aspects of this biologically and clinically important process. In this study, the expression of tenascin in the renal interstitium was immunohistochemically evaluated in 208 renal specimens during normal kidney (23 cases), acute tubular necrosis (8), acute tubulointerstitial nephritis (8), chronic primary tubulointerstitial nephritis (30), tubulointerstitial nephritis secondary to glomerular diseases of mild (46) and severe (55) degree, ischemic damage (24), and rejection (14). It was found that in normal kidney tenascin expression was limited to the medullary interstitium. In kidney with tubulointerstitial nephritis, tenascin was ubiquitously and constantly expressed in any areas with tubulointerstitial damage regardless of diagnosis, etiology, the cortical vs. medullary location of the lesions, stage of the fibrogenetic process, density of fibroblasts, or severity of interstitial inflammation in the affected areas. Indeed, strong tenascin expression was seen in areas where there was only interstitial edema or inflammation as judged by routine light microscopic preparations. In summary, this study systematically documents tenascin as a novel extracellular matrix protein selectively expressed in the medullary interstitium in normal kidney, and ubiquitously present in areas with interstitial fibrosis.

We report a 16-year-old male who developed nephrotic syndrome related to membranous glomerulopathy with clinical and serological evidence of systemic lupus erythematosus after treatment with griseofulvin. To our knowledge, this is the first case of griseofulvin-exacerbated lupus in which nephrotic syndrome has been observed.

Over a period of 5 years (from 1989 to 1993) 410 patients with benign prostatic hypertrophy (BPH) were treated by transurethral resection of the prostate (TURP). A retrospective study was conducted by the Authors to evaluate indications, surgical approaches and results. The Authors' experience is compared with literature reports.

Although long-term use of cyclosporine has been implicated in the pathogenesis of arteriolar hyalinosis, interstitial fibrosis, and glomerulosclerosis observed in the native kidneys of heart transplant recipients, it is not clear that these histologic abnormalities are entirely specific for a drug-induced toxic nephropathy. The purpose of this study was to determine whether long-standing congestive heart failure, particularly when complicated by disease processes such as atherosclerosis and hypertension, may independently predispose to the development of similar renal histopathology. Records and specimens were selected from autopsy files for evaluation of clinical profiles and kidney histology in 16 patients who died of end-stage cardiomyopathy of varying causes without having recourse to heart transplantation. The study cohort consisted of 12 men and four women. Cardiomyopathies were the result of coronary artery disease in six patients and nonischemic causes in the other 10 patients. The mean age at the time of death was 53 +/- 3 years (range 28 to 74 years). Thirteen (81%) of 16 patients had a history of hypertension. Nadir serum creatinine concentrations during the month before death were 1.7 +/- 0.2 mg/dl (range 1.2 to 3.5 mg/dl). Interstitial fibrosis, tubular atrophy, and glomerulosclerosis were present in 15 (94%) of 16 patients. Arteriosclerosis and arteriolosclerosis were found in 13 (81%) of 16 and 14 (88%) of 16 patients, respectively. A nodular pattern of arteriolar hyalinosis was observed in two patients with ischemic disease.(ABSTRACT TRUNCATED AT 250 WORDS)

We report a case of bilaterally multifocal renal oncocytomas in a patient with chronic renal disease and a long history of hypertension. Histologic study of the multiple oncocytic neoplasms with hematoxylin-eosin, periodic acid-Schiff, trichrome, and colloidal iron stains revealed novel, intracytoplasmic lumina, which were accentuated by immunoperoxidase staining with high-molecular-weight cytokeratin, epithelial membrane antigen, and Arachis hypogaea lectin. Ultrastructural studies demonstrated multiple microvilli lining the intracytoplasmic lumina. We also review the literature on bilaterally multifocal oncocytomas.

The effect of exogenous atrial natriuretic peptide (ANP) on urine excretion and glomerular filtration rate (GFR) during acute renal allograft rejection was evaluated in a canine model. Eight animals underwent simultaneous allotransplantation and unilateral native nephrectomy. No preoperative or postoperative immunosuppressive therapy was given. Acute renal function studies were performed on the allografts and companion, native kidneys following surgical exposure and mobilization on the third postoperative day. At reexploration, the allografts were found to be grossly enlarged (138 +/- 10 gm.) and contained moderate-to-marked perivascular interstitial infiltration. Glomerular filtration rate, determined by measurement of urinary inulin clearance, was significantly reduced from prenephrectomy baseline values (19 +/- 4 ml. per minute versus 32 +/- 5 ml. per minute, p < .05). During a 30 minute, intravenous ANP infusion, allograft urine flow rates increased from 1.4 +/- 0.5 ml. per minute to 3.3 +/- 0.4 ml. per minute (p < .01), and GFR increased from 19 +/- 4 ml. per minute to 24 +/- 4 ml. per minute (p < .05). During ANP infusion, mean arterial pressure declined from 136 +/- 7 mm. Hg to 116 +/- 7 mm. Hg (p < .05), and the hematocrit remained unchanged. These observations are consistent with previously described, ameliorative effects of ANP in other models of acute ischemic renal injury and provide an experimental basis for more extended studies examining the potential usefulness of ANP as adjunctive therapy in the treatment of acute renal allograft rejection.

Eight cases of congenital mesoblastic nephroma (CMN) were examined. Three CMNs were of the classical (typical) variant, two were cellular (atypical), and three showed a mixed pattern. A panel of nephron segment-specific tubular epithelial markers (the lectins Tetragonolobus purpureas, Phaseolus vulgaris erythroagglutinin, and Arachis hypogaea and antibodies to epithelial membrane antigen, cytokeratin, and Tamm-Horsfall protein) were used to differentiate epithelial structures within the tumor. Antibodies against vimentin, desmin, and muscle-specific actin were used as mesenchymal markers. A monoclonal antibody to the long (embryonic) form of polysialic acid (PSA) on the neural cell adhesion molecule was used as a putative renal oncodevelopmental marker. An antibody to proliferating cell nuclear antigen also was applied, which revealed increased proliferative rate in cellular CMNs. In addition to clearly entrapped native renal tubules, CMNs contain tubular structures with immature, dysplastic epithelium and occasional epithelial cell clusters embedded deep within the tumor. These immature tubules and clusters express distal nephron, including collecting duct markers and, occasionally, vimentin and PSA. We propose that these primitive tubules and epithelial structures may originate from the ureteric bud. An epithelial differentiation of the tumor cells also is possible. In one pure cellular CMN and two mixed CMNs the cellular component showed diffuse staining for PSA. The PSA (neural cell adhesion molecule) expression of the cellular component suggests that CMN may originate from the uninduced nephrogenic mesenchyme.

In a review of the autopsies and medical records of 22 obese patients, focal segmental glomerulosclerosis (FSGS) was present in seven. The FSGS was mild in all but one patient. The FSGS of obese patients has similar features to idiopathic FSGS; however, our findings suggest that it lacks the hyperplasia of glomerular epithelial cells, shows no predilection for the corticomedullary junction, and is probably more often seen in the hilar region of the glomeruli. FSGS or glomerulomegaly was not associated with the degree of obesity. We demonstrated lipid deposition in the kidney of obese patients. Obese patients with FSGS, compared to those without FSGS, had higher blood cholesterol (P < 0.10) and higher triglyceride levels (P < 0.01). The mean heart weight of obese patients with FSGS was greater than that of patients without FSGS (P < 0.01). Also, obese patients with FSGS had larger glomeruli (246 +/- 33 microns) than obese patients without FSGS (218 +/- 16 microns) (P < 0.05). These findings suggest that cardiomegaly with hemodynamic changes and glomerular hyperfiltration may play a significant role in the glomerulomegaly and FSGS of obese patients. The secondary or contributory role of lipids in the development of the FSGS of obese patients remains to be determined.

The post insult administration of vascular decongestants has resulted in attenuation of experimental acute renal failure (ARF) following the introduction of various nephrotoxins including drugs, heavy metals, and endotoxin. In the present study, the dose-dependent effects of a novel methylxanthine, HWA-138, were studied in the glycerol-induced murine model of ARF. Renal function, assessed by serial inulin clearances at 24 and 48 h after glycerol injection, urinary electrolyte excretion rates, and renal morphology, was compared between controls and those given glycerol and single i.v. doses of 0.1, 0.5, 1.0, 5.0, and 10.0 mg/kg of HWA-138, or physiologic saline. Whereas significant renal dysfunction was found in all animal groups given glycerol, the mean inulin clearance values of animals given HWA-138 1 mg/kg closely approximated values found in control rats. There were no changes in renal electrolyte excretion rates in animals given HWA-138 compared with relative natriuresis found in untreated glycerol ARF rat. Although a modest decrease in medullary congestion was associated with rats given 1 mg/kg of HWA-138, there was no obvious structural improvement found with HWA-138. The present data provide further evidence of the potential of methylxanthines in the glycerol-ARF murine model.

Sickle cell disease is known to cause glomerulopathy, including focal segmental glomerulosclerosis (FSGS). Patients who have sickle cell glomerulopathy with FSGS are thought to have a poorer prognosis than patients who have sickle cell glomerulopathy without this lesion. The former patients are more likely to have persistent proteinuria and eventually develop end-stage renal disease. We present a boy with sickle cell glomerulopathy and FSGS who is younger than patients with similar findings reported previously. The histopathology of his renal lesions is remarkable for segmental ultrastructural changes in the glomerular basement membranes and endothelial cells. We speculate that these changes are precursory to the pathogenesis of glomerular sclerosis in patients with sickle cell disease.

Dose-limiting nephrotoxicity has hampered the clinical usefulness of amphotericin-B (AmpB). Recently, vascular decongestants, such as pentoxifylline, have shown benefit in reducing drug-associated renal damage of AmpB in rats. The present study investigated a dose-dependent protection of a structurally similar methylxanthine, HWA-448, in the candidiasis rat model given a single dose of AmpB. Forty-eight hours after inoculation with Candida albicans, each rat was treated with 0.8 mg/kg of AmpB or sterile water; animals were further randomized to receive 0.5, 1, 5, or 10 mg/kg i.v. of HWA-448 or saline given every 12 h for 3 doses. Kidney fungal counts, morphology, and renal function were compared between treatment groups upon completion of the study. Rats administered AmpB with HWA-448 had markedly improved renal function compared with those given AmpB alone; these effects were independent of the administered dose of HWA-448. The antifungal effect of AmpB was not impaired with concomitant HWA-448. Marked accumulation of granulomas and organisms was found in all rat groups. In summary, coadministration of low doses of HWA-448 attenuated the dose-limiting nephrotoxicity without impairing the antifungal effect of AmpB.

Although squamous cell carcinoma of the esophagus occurs with increased incidence in primary achalasia, esophageal adenocarcinoma has been considered rare in this condition. We report a patient with long-standing achalasia in whom adenocarcinoma of the esophagus occurred many years after Heller esophagomyotomy, presumably related to Barrett's esophagus complicating gastro-esophageal reflux disease.

Although a significant interaction between cyclosporine and amphotericin-B (AmpB) has been observed clinically, these findings have not been duplicated in animal studies. A total of 64 male albino rats were used in single- and multiple-dose experiments with AmpB and CsA in the absence or presence of systemic Candida infection. No significant differences in glomerular filtration rate were found in rats given single i.v. doses of AmpB 1 mg/kg compared with AmpB and CsA. Furthermore, rats given i.p. AmpB 1 mg/kg and CsA 10 mg/kg daily for 10 days showed no significant differences in GFR compared with animals given CsA alone. Morphology and CsA whole-blood pharmacokinetics were not different between groups administered single-dose CsA, AmpB, or the combination; similarities also existed with multiple-dose studies. In an attempt to mimic the clinical setting, 2 groups of rats were administered i.p. CsA 10 mg/kg/day for 10 days followed by inoculation of Candida albicans. After 48 hr, a single i.v. dose of AmpB 1.0 mg/kg was associated with a 33% decline in GFR compared with those given sterile water (P less than 0.05). Systemic clearance of CsA was markedly reduced in candidiasis rats administered AmpB compared with controls given sterile water. A significant reduction in renal Candida colony-forming units was found in rats given CsA and AmpB compared with those administered CsA alone. These data suggest that the presence of systemic Candida highlights the interaction of CsA and AmpB in the rat model.

A patient with acquired immune deficiency syndrome (AIDS) who presented with right testicular swelling is described. Sonography demonstrated diffuse enlargement and inhomogeneity of the testicle with central hypoechoic areas. Testicular abscesses were seen at surgery and Mycobacterium tuberculosis was cultured from the surgical specimen. Tuberculosis should be considered in the differential diagnosis of testicular enlargement or abscess formation in AIDS.

Administration of maleic acid to the rat is used as an experimental model of Fanconi's syndrome. To determine the site and extent of morphologic injury within the kidney after maleic acid administration, we systematically examined renal tissue using light, transmission electron, and scanning electron microscopy. Tissue was studied either immediately or 24 hours after rats received maleic acid, 200 mg. or 400 mg. per kg. of body weight, and was compared with tissue from controls. In kidneys of maleic acid-treated rats, evidence of injury was observed only in cells of the late pars convoluta and the pars recta in the medullary rays of the cortex and in the outer stripe of the medulla. Injured cells were characterized by an increase in cytoplasmic density, accumulation of numerous small vesicles in the apical region of the cells, abnormal-appearing mitochondria with compressed cristal membranes and flocculent densities, and focal loss of microvilli. Injury was apparent immediately after maleic acid administration and progressed to extensive necrosis by 24 hours after either the 200- or 400-mg. per kg. dose. Except for the presence of granular and hyaline casts in the lumena, the loops of Henle and distal convoluted tubules were normal. Collecting ducts in the outer medulla, but not in the cortex, medullary rays, or inner medulla, had significantly increased numbers of dark cells per total cell population when compared with controls (p less than 0.005). This increase in dark cells may represent an adaptive response of the medullary collecting duct to the functional abnormalities of maleic acid-induced Fanconi's syndrome. Collecting ducts showed no evidence of cell injury or necrosis. These observations provide evidence that maleic acid, like many other renal toxins, produces tubular injury and necrosis only in the proximal tubules, primarily in the medullary rays, and outer stripe of the medulla, and not in the distal tubules.

Three renal transplant recipients were studied who developed the hemolytic uremic syndrome (HUS) during cyclosporine (CsA) immunosuppression. All patients displayed characteristic findings including normocytic, normochromic anemia, thrombocytopenia, erythrocyte morphologic abnormalities, increased numbers of reticulocytes, bone marrow hyperplasia, and renal failure. The clinical studies support the diagnosis of an extrinsic hemolytic process. Renal biopsy specimens demonstrated fibrin deposition and glomerular thrombosis. The renal failure was not responsive to antirejection therapy. The first patient was converted to azathioprine and consequently had a gradual improvement in renal function. Failure to convert the second patient resulted in adequate immunosuppression and subsequent graft loss. The third patient's improvement corresponded with a moderate CsA dose reduction. The occurrence of HUS in these patients represents a de novo presentation after CsA immunosuppression. An analysis of these cases indicates that CsA should be discontinued if HUS persists after moderate dose reduction.

Three family members, at initial evaluation, had generalized comedonal lesions with histologic changes of acantholysis and dyskeratosis. A total of nine cases of this entity, termed familial dyskeratotic comedones, have been documented in the literature. It appears to have autosomal dominant inheritance and onset in childhood or adolescence. Lesions are asymptomatic except for occasional pruritus or inflammation, and general health is undisturbed. A history of acne vulgaris is seen in four of nine patients and is the only associated skin disease. Treatment with oral isotretinoin produced no improvement in two patients. Electron microscopy revealed changes similar to those seen in Darier's disease.

Histochemical techniques utilizing Tetragonolobus lotus (proximal tubules), Arachis hypogaea (distal nephron, i.e., distal convoluted tubules and collecting ducts), and antibodies against Tamm-Horsfall protein (thick ascending limbs of Henle) were used to determine the site of origin of renal cysts in five children with autosomal recessive polycystic kidney disease (ARPKD) and three patients with glomerulocystic disease (GCD) presenting in the 1st year of life. The findings support a distal nephron origin for the cysts in the children who had ARPKD, whereas the majority of cysts in the children with GCD were confirmed as having a glomerular origin. Tamm-Horsfall protein was identified in the cysts of both ARPKD and GCD; this finding suggests free communication between some of the cysts with the thick ascending limb of Henle. An unexpected finding was the frequent presence of cysts surrounded by muscle fibers. We suggest that these cysts are of collecting duct origin.