Pre-treatment absolute lymphocyte count predicts for improved survival in human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma.

BACKGROUND: The prognostic value of pretreatment complete blood count (CBC) data, including absolute lymphocyte count (ALC) and the neutrophil-to-lymphocyte ratio (NLR), has been reported for many diseases with decreased ALC and increased absolute neutrophil count (ANC) and NLR values correlating with worse outcomes. There is minimal data relating these hematologic parameters to oropharyngeal squamous cell carcinoma (OPSCC) prognosis. This study evaluates the prognostic value of pretreatment CBC data in OPSCC on overall survival (OS) and progression-free survival (PFS) in relation to HPV status. METHODS: A single-institutional retrospective review of patients with pretreatment hematologic data who received radiation for OPSCC was performed. Univariate and multivariate (UVA/MVA) Cox proportional hazard regression analyses were performed to identify prognostic variables. Translational studies related outcomes to the degree of tumor-infiltrating lymphocytes (TILs) in histologic specimens. RESULTS: From 2007 to 2018, 201 patients were treated for OPSCC. Median follow-up was 40 months. 3-year OS was 86.2% in the HPV-positive cohort, 46.3% for HPV-negative. Median NLR was 3.04. NLR ≥ 3 was associated with worse PFS (HR 1.67, p = 0.044. In the subset of 158 HPV + patients, MVA revealed increasing ALC to be associated with improved OS (HR 0.53; p = 0.040) and PFS (HR = 0.48; p = 0.0075). On UVA, high-TIL infiltration at diagnosis was associated with improved OS. CONCLUSION: In a cohort of HPV + OPSCC patients, increasing ALC is associated with improved OS and PFS. Our study is the first to identify pre-treatment ALC as an independent prognostic factor in HPV-associated OPSCC.

Massive paediatric pulmonary haemorrhage in Dieulafoy's disease: Roles of CT angiography, embolisation and bronchoscopy.

Acute, major pulmonary haemorrhage in children, is rare, may be life-threatening and at times presents atypically. Dieulafoy's disease of the bronchus presenting with recurrent or massive hemoptysis was first described in adults. Prior to reviewing the literature, we report an illustrative case of bronchial Dieulafoy's disease (BDD) in a child presenting unusually with massive apparent hematemesis. The source of bleeding is a bronchial artery that fails to taper as it terminates within the bronchial submucosa. A high index of suspicion is required to identify such lesions via radiological imaging and the role of bronchial artery embolisation is highlighted with video images of angiography included.

Randomized clinical trial of pigtail catheter versus chest tube in injured patients with uncomplicated traumatic pneumothorax.

BACKGROUND: Small pigtail catheters appear to work as well as the traditional large-bore chest tubes in patients with traumatic pneumothorax, but it is not known whether the smaller pigtail catheters are associated with less tube-site pain. This study was conducted to compare tube-site pain following pigtail catheter or chest tube insertion in patients with uncomplicated traumatic pneumothorax. METHODS: This prospective randomized trial compared 14-Fr pigtail catheters and 28-Fr chest tubes in patients with traumatic pneumothorax presenting to a level I trauma centre from July 2010 to February 2012. Patients who required emergency tube placement, those who refused and those who could not respond to pain assessment were excluded. Primary outcomes were tube-site pain, as assessed by a numerical rating scale, and total pain medication use. Secondary outcomes included the success rate of pneumothorax resolution and insertion-related complications. RESULTS: Forty patients were enrolled. Baseline characteristics of 20 patients in the pigtail catheter group were similar to those of 20 patients in the chest tube group. No patient had a flail chest or haemothorax. Pain scores related to chest wall trauma were similar in the two groups. Patients with a pigtail catheter had significantly lower mean(s.d.) tube-site pain scores than those with a chest tube, at baseline after tube insertion (3.2(0.6) versus 7.7(0.6); P < 0.001), on day 1 (1.9(0.5) versus 6.2(0.7); P < 0.001) and day 2 (2.1(1.1) versus 5.5(1.0); P = 0.040). The decreased use of pain medication associated with pigtail catheter was not significantly different. The duration of tube insertion, success rate and insertion-related complications were all similar in the two groups. CONCLUSION: For patients with a simple, uncomplicated traumatic pneumothorax, use of a 14-Fr pigtail catheter is associated with reduced pain at the site of insertion, with no other clinically important differences noted compared with chest tubes. REGISTRATION NUMBER: NCT01537289 (http://clinicaltrials.gov).

Angiotensin-(1-7) inhibits vascular remodelling in rat jugular vein grafts via reduced ERK1/2 and p38 MAPK activity.

This study evaluated the effect of angiotensin (Ang)-(1-7) on vascular remodelling in a rat autologous jugular vein graft model in which rats underwent autologous jugular vein graft transplantation (Ang-[1-7] and control groups) or sham surgery (sham group). The animals received continuous jugular infusion of Ang-(1-7) at 25 µg/kg per h (Ang-[1-7] group) or normal saline (control and sham groups) starting 3 days after surgery. Ang-(1-7) infusion reduced venous graft hyperplasia, vascular remodelling, extracellular signal-regulated kinase 1/2 (ERK1/2) activation, p38 mitogen-activated protein kinase (MAPK) activation and levels of proliferating cell nuclear antigen and α-smooth muscle actin compared with control animals. The vascular tissue Ang II level was higher in Ang-(1-7) and control rats than in sham animals. These findings suggest that Ang-(1-7) acts by inhibiting the activation of ERK1/2 and p38 MAPK in vascular tissue. The use of exogenous Ang-(1-7) could improve the outcome of vein grafting through the attenuation of vascular remodelling.

Memory T-cell predominance following T-cell depletional therapy derives from homeostatic expansion of naive T cells.

T-cell depletion reportedly leads to alterations in the T-cell compartment with predominant survival of memory phenotype CD4 T cells. Here, we asked whether the prevalence of memory T cells postdepletion results from their inherent resistance to depletion and/or to the homeostatic expansion of naive T cells and their phenotypic conversion to memory, which is known to occur in lymphopenic conditions. Using a 'mosaic memory' mouse model with trackable populations of alloreactive memory T cells, we found that treatment with murine antithymocyte globulin (mATG) or antilymphocyte serum (ALS) effectively depleted alloreactive memory CD4 T cells, followed by rapid homeostatic proliferation of endogenous CD4 T cells peaking at 4 days postdepletion, with no homeostatic advantage to the antigen-specific memory population. Interestingly, naive (CD44lo) CD4 T cells exhibited the greatest increase in homeostatic proliferation following mATG treatment, divided more extensively compared to memory (CD44hi) CD4 T cells and converted to a memory phenotype. Our results provide novel evidence that memory CD4 T cells are susceptible to lymphodepletion and that the postdepletional T-cell compartment is repopulated to a significant extent by homeostatically expanded naive T cells in a mouse model, with important important implications for immune alterations triggered by induction therapy.

A new technique for measurement of pharyngeal pH: normal values and discriminating pH threshold.

INTRODUCTION: Identifying gastroesophageal reflux disease as the cause of respiratory and laryngeal complaints is difficult and depends largely on the measurements of increased acid exposure in the upper esophagus or ideally the pharynx. The current method of measuring pharyngeal pH environment is inaccurate and problematic due to artifacts. A newly designed pharyngeal pH probe to avoid these artifacts has been introduced. The aim of this study was to use this probe to measure the pharyngeal pH environment in normal subjects and establish pH thresholds to identify abnormality. METHODS: Asymptomatic volunteers were studied to define the normal pharyngeal pH environment. All subjects underwent esophagram, esophageal manometry, upper and lower esophageal pH monitoring with a dual-channel pH catheter and pharyngeal pH monitoring with the new probe. Analyses were performed at 0.5 pH intervals between pH 4 and 6.5 to identify the best discriminating pH threshold and calculate a composite pH score to identify an abnormal pH environment. RESULTS: The study population consisted of 55 normal subjects. The pattern of pharyngeal pH environment was significantly different in the upright and supine periods and required different thresholds. The calculated discriminatory pH threshold was 5.5 for upright and 5.0 for supine periods. The 95th percentile values for the composite score were 9.4 for upright and 6.8 for supine. CONCLUSION: A new pharyngeal pH probe which detects aerosolized and liquid acid overcomes the artifacts that occur in measuring pharyngeal pH with existing catheters. Discriminating pH thresholds were selected and normal values defined to identify patients with an abnormal pharyngeal pH environment.

Recurrence of intramucosal esophageal adenocarcinoma arising in a former esophagostomy site: a unique case report.

A 75-year-old male with a long history of gastroesophageal reflux symptoms developed adenocarcinoma proximally within a long segment of Barrett's esophagus. He was taken for esophagectomy and gastric pull-up, but intraoperatively, he was found to have a marginal blood supply in the gastric tube. A temporary left-sided esophagostomy was created with the gastric tube sutured to the left sternocleidomastoid muscle in the neck. Pathology showed an intramucosal adenocarcinoma, limited to the muscularis mucosa with surrounding high-grade dysplasia and intestinal metaplasia. The proximal esophageal margin showed no tumor cells, but there was low-grade dysplasia within Barrett's esophagus. He was reconstructed after several months, and 2 years after reconstruction, the patient noticed a nodule at the former esophagostomy site. Biopsy revealed an implant metastasis of esophageal adenocarcinoma. Here, we review the literature and discuss the possible etiology.

Fermentation of calcium-fortified soymilk with Lactobacillus: effects on calcium solubility, isoflavone conversion, and production of organic acids.

The objective of this study was to enhance calcium solubility and bioavailability from calcium-fortified soymilk by fermentation with 7 strains of Lactobacillus, namely, L. acidophilus ATCC 4962, ATCC33200, ATCC 4356, ATCC 4461, L. casei ASCC 290, L. plantarum ASCC 276, and L. fermentum VRI-003. The parameters that were used are viability, pH, calcium solubility, organic acid, and biologically active isoflavone aglycone content. Calcium-fortified soymilk made from soy protein isolate was inoculated with these probiotic strains, incubated for 24 h at 37 degrees C, then stored for 14 d at 4 degrees C. Soluble calcium was measured using atomic absorption spectrophotometry (AA). Organic acids and bioactive isoflavone aglycones, including diadzein, genistein, and glycetein, were measured using HPLC. Viability of the strains in the fermented calcium-fortified soymilk was > 8.5 log(10) CFU/g after 24 h fermentation and this was maintained for 14-d storage at 4 degrees C. After 24 h, there was a significant increase (P < 0.05) in soluble calcium. L. acidophilus ATCC 4962 and L. casei ASCC 290 demonstrated the highest increase with 89.3% and 87.0% soluble calcium after 24 h, respectively. The increase in calcium solubility observed was related to lowered pH associated with production of lactic and acetic acids. Fermentation significantly increased (P < 0.05) the level of conversion of isoflavones into biologically active aglycones, including diadzein, genistein, and glycetein. Our results show that fermenting calcium-fortified soymilk with the selected probiotics can potentially enhance the calcium bioavailability of calcium-fortified soymilk due to increased calcium solubility and bioactive isoflavone aglycone enrichment.

Acute exercise-induced nitric oxide production contributes to upregulation of circulating endothelial progenitor cells in healthy subjects.

Exercise has been proved to promote the number and activity of circulating endothelial progenitor cells (EPCs) in humans, which contributes to improvement in endothelial function and maintenance of cardiovascular homoeostasis. However, the mechanism underlying the effect of exercise on circulating EPCs in healthy subjects is not completely understood. Here, we investigated whether the regulation of acute exercise on circulating EPCs is associated with nitric oxide (NO), vascular endothelial growth factors (VEGF) and granulocyte macrophage colony stimulating factor (GM-CSF) known to modulate circulating EPCs in healthy subjects. A total of 16 healthy male volunteers underwent a modified Bruce treadmill acute exercise protocol. The number and activity of circulating EPCs, as well as the levels of NO-VEGF and GM-CSF in plasma and culture medium before and after exercise in healthy subjects were measured. The number and activity of circulating EPCs after acute exercise were significantly higher than those before exercise in healthy subjects. In parallel, acute exercise significantly enhanced plasma NO level in healthy subjects. There is a significant linear regression relationship between the enhanced plasma NO level and increased number or activity of circulating EPCs. However, no change of plasma VEGF and GM-CSF level was observed after acute exercise. The secretion of NO-VEGF and GM-CSF by cultured EPCs remained unchanged in response to acute exercise. The present study demonstrates for the first time that acute exercise-induced NO production contributes to upregulation of circulating EPCs in healthy subjects, which suggests that NO plays an important role in the regulation of exercise on circulating EPCs.

Shear stress increases Cu/Zn SOD activity and mRNA expression in human endothelial progenitor cells.

Endothelial progenitor cells (EPCs) are involved in endothelial repair. However, the function of EPCs is impaired in the presence of cardiovascular risk factors. Therefore, upregulation of functional gene expression and bioactive substance production such as superoxide dismutase (SOD) activity and mRNA expression in EPCs may contribute to the maintenance of EPC-related endothelial repair. EPCs from human peripheral blood mononuclear cells were exposed to in vitro 5, 15 and 25 dyn/cm(2) shear stress for 5, 15 and 25 h, respectively. Shear stress in a dose- and time-dependent fashion increased Cu/Zn SOD activity of human EPCs. Shear stress also upregulated the Cu/Zn SOD mRNA expression of human EPCs, indicating that an increase in Cu/Zn SOD activity induced by shear stress was mediated by enhanced transcription. Our data are the first time to show that in vitro shear stress enhances mRNA expression and activity of Cu/Zn SOD in human EPCs, suggesting that shear stress can be used as a novel Means of manipulation to improve functional potential of EPCs. The augmentation in copper/zinc-containing enzyme (Cu/Zn SOD), with subsequent accelerated superoxide anion (O(2)(-)) inactivation, might increase locally nitric oxide (NO) biological availability, which contributes to EPC-related vascular protection.

Arterial elasticity identified by pulse wave analysis and its relation to endothelial function in patients with coronary artery disease.

Patients with coronary artery disease (CAD) have impaired endothelial function. Arterial elasticity is modulated by endothelial function. The association between arterial elasticity and endothelial function has not been reported in patients with CAD. The present study was designed to investigate whether endothelial dysfunction contributes to impaired arterial elasticity. Thirty patients with CAD and 30 control subjects were recruited. Large and small artery elasticity indices were non-invasively assessed using pulse wave analysis. Brachial artery endothelium-dependent and -independent function were assessed by vascular response to flow-mediated vasodilation (FMD) and sublingual nitroglyceride (NTG), respectively. C1 large artery elasticity index was not different in the CAD group compared with the control group. However, C2 small artery elasticity index was significantly reduced in the CAD group compared with the control group. Flow-mediated vasodilation (FMD) was also impaired in the CAD group compared with the control group. Flow-mediated vasodilation (FMD) in the brachial artery correlated with C2 small arterial elasticity index. But NTG-mediated brachial artery vasodilation was similar between the two groups. The present findings suggest that the patients with CAD have reduced C2 small arterial elasticity index and impaired FMD. Endothelial dysfunction is involved in diminished arterial elasticity, suggesting that C2 small arterial elasticity index is a novel surrogate measure for the clinical evaluation of endothelial function.

Generation and functional capacity of polyclonal alloantigen-specific memory CD4 T cells.

Alloreactive memory T cells can significantly impact graft survival due to their enhanced functional capacities, diverse tissue distribution and resistance to tolerance induction and depletional strategies. However, their role in allograft rejection is not well understood primarily due to the lack of suitable in vivo models. In this study, we use a novel approach to generate long-lived polyclonal alloreactive memory CD4 T cells from adoptive transfer of alloantigen-activated precursors into mouse hosts. We demonstrate that CD25 upregulation is a marker for precursors to alloantigen-specific memory and have created a new mouse model that features an expanded population of polyclonal alloreactive memory T cells that is distinguishable from the naive T-cell population. Furthermore, we show that alloreactive memory T cells exhibit rapid recall effector responses with predominant IFN-gamma and IL-2 production, and mediate vigorous allograft rejection. Interestingly, while we found a heterogeneous distribution of allomemory T cells in lymphoid and nonlymphoid tissues, they were all predominantly of the effector-memory (CD62Llo) phenotype. Our results present a unique model for the generation and tracking of polyclonal allospecific memory CD4 T cells in vivo and reveal insights into the distinct and robust nature of alloreactive T-cell memory.

Neointimal responses 3 months after (32)P beta-emitting stent placement.

PURPOSE: Studies have shown a potential benefit of brachytherapy in preventing restenosis. However, the effects of intravascular radiation on arterial healing have not been well-established. The purpose of this study was to explore the histologic changes following placement of beta-emitting radioactive stents in arteries focusing on intimal responses and endothelialization. METHODS AND MATERIALS: 3.0-mm beta-emitting (32)P stents (6-microCi and 24-microCi) were placed in rabbit iliac arteries with nonradioactive stents serving as controls. Animals were euthanized at 3 months and histologic assessment, morphometry, and analysis of endothelialization were performed. RESULTS: The lumen areas of 24-microCi stents (4.24 +/- 0.22 mm(2), p < 0.0007) and 6-microCi stents (4.23 +/- 0.49 mm(2), p < 0.01) were larger than control stents (3.64 +/- 0.44 mm(2)). The mean lumen percent stenosis was 11. 4 +/- 3.0% in the 24-microCi stents (p < 0.007 vs. 6-microCi stents and p < 0.0001 vs. control stents), 18.7 +/- 6.4% in the 6-microCi stents (p < 0.02 vs. control stents), and 25.0 +/- 4.9% in control stents. Neointimal area was least in the 24-microCi stent (54.2% smaller than controls and 42.7% smaller than 6-microCi); the neointimal area of the 6-microCi stents was 20.0% less than controls. The control stent neointima consisted of smooth muscle cells in a proteoglycan and collagen matrix. In contrast, the intima of radioactive stents showed persistent fibrin thrombus with nonconfluent areas of matrix. Actin-positive intimal cell density was reduced with radioactive stenting, but intimal cell proliferation was increased. Evans blue staining, an indicator of increased endothelial permeability, was present on 86 +/- 9% of the stented segment of 6-microCi stents vs. 10 +/- 11% in controls (p < 0.0001). Scanning electron microscopy demonstrated endothelialization of 97 +/- 8% of the intimal surface of control stents; in contrast, the midportion of the 6-microCi stents remained nonendothelialized, and only 33 +/- 15% (p < 0.0001) of the entire stent surface was endothelialized. CONCLUSIONS: (32)P beta-emitting stents reduce neointimal growth, but healing is incomplete with poor endothelialization at 3 months. Longer-term studies with complete arterial healing are needed to determine whether there is sustained neointimal inhibition by stent-delivered brachytherapy.

Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death.

BACKGROUND: Coronary thrombosis has been reported to occur most frequently in lipid-rich plaques with rupture of a thin fibrous cap and contact of the thrombus with a pool of extracellular lipid. However, the frequency of coronary artery thrombosis with or without fibrous cap rupture in sudden coronary death is unknown. In this study, we compared the incidence and morphological characteristics of coronary thrombosis associated with plaque rupture versus thrombosis in eroded plaques without rupture. METHODS AND RESULTS: Fifty consecutive cases of sudden death due to coronary artery thrombosis were studied by histology and immunohistochemistry. Plaque rupture of a fibrous cap with communication of the thrombus with a lipid pool was identified in 28 cases. Thrombi without rupture were present in 22 cases, all of which had superficial erosion of a proteoglycan-rich plaque. The mean age at death was 53 +/- 10 years in plaque rupture cases versus 44 +/- 7 years in eroded plaques without rupture (P < .02). In the plaque-rupture group, 5 of 28 (18%) were women versus 11 of 22 (50%) with eroded plaques (P = .03). The mean percent luminal area stenosis was 78 +/- 12% in plaque rupture and 70 +/- 11% in superficial erosion (P < .03). Plaque calcification was present in 69% of ruptures versus 23% of erosions (P < .002). In plaque ruptures, the fibrous cap was infiltrated by macrophages in 100% and T cells in 75% of cases compared with 50% (P < .0001) and 32% (P < .004), respectively, in superficial erosions. Clusters of smooth muscle cells adjacent to the thrombi were present in 95% of erosions versus 33% of ruptures (P < .0001). HLA-DR expression was more often seen in macrophages and T cells in ruptures (25 of 28 cases) compared with expression in macrophages in superficial erosion arteries (8 of 22 cases, P = .0002). CONCLUSIONS: Erosion of proteoglycan-rich and smooth muscle cell-rich plaques lacking a superficial lipid core or plaque rupture is a frequent finding in sudden death due to coronary thrombosis, comprising 44% of cases in the present study. These lesions are more often seen in younger individuals and women, have less luminal narrowing and less calcification, and less often have foci of macrophages and T cells compared with plaque ruptures.

Sudden coronary death. Frequency of active coronary lesions, inactive coronary lesions, and myocardial infarction.

BACKGROUND: The reported frequency of active coronary lesions (plaque rupture and coronary thrombosis) in sudden death due to coronary artery atherosclerosis (sudden coronary death) has varied from < 20% to > 80% of cases in previous series. In hearts lacking an active coronary lesion, sudden death has usually been attributed to a healed myocardial infarction. The purpose of the present study was to determine the frequency of active and inactive coronary lesions and myocardial infarction in individuals with sudden coronary death. METHODS AND RESULTS: The hearts of persons who died as a result of sudden coronary death underwent perfusion-fixation and postmortem angiography. An active coronary lesion was defined as a disrupted plaque, luminal fibrin/platelet thrombus, or both. We defined an inactive lesion as having a cross-sectional luminal stenosis of > or = 75% with neither plaque disruption nor luminal thrombus. Ninety hearts were examined (from 72 men and 18 women; mean age at the time of death, 51 +/- 10 years). Acute myocardial infarction was present in 19 (21% [acute myocardial infarction only in 9, both acute and healed myocardial infarction in 10]), healed myocardial infarction only in 37 (41%), and no myocardial infarction in 34 (38%). Active coronary lesions were identified in 51 (57%): acute thrombi plus disrupted plaques in 27, acute thrombi only in 21, and disrupted plaques only in 3. In hearts with acute myocardial infarction, active coronary lesions were significantly more prevalent than in hearts with only healed myocardial infarction or hearts lacking an acute or a healed myocardial infarction (89%, 46%, and 50%, respectively; P < .005). Hearts without acute or healed myocardial infarction and without active lesions were similar to hearts with active lesions with respect to heart weight and severity of epicardial coronary disease. CONCLUSIONS: Acute changes in coronary plaque morphology (thrombus, plaque disruption, or both) were found in 57% of cases of sudden coronary death. In hearts with myocardial scars and no acute infarction, active coronary lesions were identified in 46% of cases. Neither myocardial infarction (acute or healed) nor an active coronary lesion was present in 19% of hearts.

Comparison of cardiac findings in patients with mitral valve prolapse who die suddenly to those who have congestive heart failure from mitral regurgitation and to those with fatal noncardiac conditions.

Sudden death occurs in a small but important subset of patients with mitral valve prolapse (MVP). Clinical criteria for identifying patients at risk for sudden death have been elusive. To determine if certain morphologic characteristics were present in hearts from patients with sudden cardiac death and MVP, autopsy hearts from persons with sudden death and isolated MVP who were previously asymptomatic or had a history of cardiac arrhythmias (n = 27) were compared with (1) hearts from patients with congestive heart failure (CHF) and mitral regurgitation (MR) secondary to MVP (n = 14), and (2) hearts from persons dying from non-cardiac causes in which MVP was an incidental finding (n = 19). Patients who died suddenly were younger than both patients with MR/CHF and incidental cases (37 +/- 10 vs 65 +/- 16 and 58 +/- 21 years, respectively, p less than 0.001). Mitral valve annular circumference, anterior and posterior mitral valve leaflet lengths, posterior mitral valve thickness, and presence and extent of endocardial plaque were greater in hearts from patients with sudden death than hearts from those with incidental MVP. Hearts from patients with MR/CHF weighed significantly more, had greater left and right atrial cavity sizes and left ventricular cavity diameter than hearts from both sudden death and incidental cases.

Remission of nephrotic syndrome in amyloidosis associated with a hypernephroma.

Nephrotic syndrome due to renal amyloidosis in association with hypernephroma underwent gradual but complete remission with loss of proteinuria after unilateral nephrectomy. Remission persisted for over five years despite the development of intracranial metastatic disease and the administration of dexamethasone, but relapse occurred 6 months before eventual death. This case history appears to be unique amongst the descriptions of tumor-associated amyloidosis.

Nephrotic syndrome and hepatitis in early syphilis.

A 54 year old man presented with features of acute hepatitis and the nephrotic syndrome. A diagnosis of active syphilis was only made by chance after extensive investigation. Syphilis should be considered in the differential diagnosis of both acute hepatitis and the nephrotic syndrome occurring separately as well as together.