case presentation nephrology

VICTORIA J. SHARP, MD, DANIEL K. LEE, MD, AND ERIC J. ASKELAND, MD

A more recent article on  office-based urinalysis  is available.

Am Fam Physician. 2014;90(8):542-547

Author disclosure: No relevant financial affiliations.

Urinalysis is useful in diagnosing systemic and genitourinary conditions. In patients with suspected microscopic hematuria, urine dipstick testing may suggest the presence of blood, but results should be confirmed with a microscopic examination. In the absence of obvious causes, the evaluation of microscopic hematuria should include renal function testing, urinary tract imaging, and cystoscopy. In a patient with a ureteral stent, urinalysis alone cannot establish the diagnosis of urinary tract infection. Plain radiography of the kidneys, ureters, and bladder can identify a stent and is preferred over computed tomography. Asymptomatic bacteriuria is the isolation of bacteria in an appropriately collected urine specimen obtained from a person without symptoms of a urinary tract infection. Treatment of asymptomatic bacteriuria is not recommended in nonpregnant adults, including those with prolonged urinary catheter use.

Urinalysis with microscopy has proven to be an invaluable tool for the clinician. Urine dipstick testing and microscopy are useful for the diagnosis of several genitourinary and systemic conditions. 1 , 2 In 2005, a comprehensive review of urinalysis was published in this journal. 3 This article presents a series of case scenarios that illustrate how primary care physicians can utilize the urinalysis in common clinical situations.

Microscopic Hematuria: Case 1

Microscopic hematuria is common and has a broad differential diagnosis, ranging from completely benign causes to potentially invasive malignancy. Causes of hematuria can be classified as glomerular, renal, or urologic 3 – 5 ( Table 1 6 ) . The prevalence of asymptomatic microscopic hematuria varies among populations from 0.18% to 16.1%. 4 The American Urological Association (AUA) defines asymptomatic microscopic hematuria as three or more red blood cells per high-power field in a properly collected specimen in the absence of obvious causes such as infection, menstruation, vigorous exercise, medical renal disease, viral illness, trauma, or a recent urologic procedure. 5 Microscopic confirmation of a positive dipstick test for microscopic hematuria is required. 5 , 7

DIAGNOSTIC APPROACH

Case 1: microscopic hematuria.

A 58-year-old truck driver with a 30-year history of smoking one pack of cigarettes per day presents for a physical examination. He reports increased frequency of urination and nocturia, but does not have gross hematuria. Physical examination reveals an enlarged prostate. Results of his urinalysis with microscopy are shown in Table 2 .

Based on this patient's history, symptoms, and urinalysis findings, which one of the following is the most appropriate next step?

A. Repeat urinalysis in six months.

B. Obtain blood urea nitrogen and creatinine levels, perform computed tomographic urography, and refer for cystoscopy.

C. Treat with an antibiotic and repeat the urinalysis with microscopy.

D. Inform him that his enlarged prostate is causing microscopic hematuria, and that he can follow up as needed.

E. Perform urine cytology to evaluate for bladder cancer.

The correct answer is B .

For the patient in case 1 , because of his age, clinical history, and lack of other clear causes, the most appropriate course of action is to obtain blood urea nitrogen and creatinine levels, perform computed tomographic urography, and refer the patient for cystoscopy. 5 An algorithm for diagnosis, evaluation, and follow-up of patients with asymptomatic microscopic hematuria is presented in Figure 1 . 5 The AUA does not recommend repeating urinalysis with microscopy before the workup, especially in patients who smoke, because tobacco use is a risk factor for urothelial cancer ( Table 3 ) . 5

A previous article in American Family Physician reviewed the American College of Radiology's Appropriateness Criteria for radiologic evaluation of microscopic hematuria. 8 Computed tomographic urography is the preferred imaging modality for the evaluation of patients with asymptomatic microscopic hematuria. 5 , 8 It has three phases that can detect various causes of hematuria. The non–contrast-enhanced phase is optimal for detecting stones in the urinary tract; the nephrographic phase is useful for detecting renal masses, such as renal cell carcinoma; and the delayed phase outlines the collecting system of the urinary tract and can help detect urothelial malignancies of the upper urinary tract. 9 Although the delayed phase can detect some bladder masses, it should not replace cystoscopy in the evaluation for bladder malignancy. 9 After a negative microscopic hematuria workup, the patient should continue to be followed with yearly urinalysis until at least two consecutive normal results are obtained. 5

In patients with microscopic hematuria, repeating urinalysis in six months or treating empirically with antibiotics could delay treatment of potentially curable diseases. It is unwise to assume that benign prostatic hyperplasia is the explanation for hematuria, particularly because patients with this condition typically have risk factors for malignancy. Although urine cytology is typically part of the urologic workup, it should be performed at the time of cystoscopy; the AUA does not recommend urine cytology as the initial test. 5

Dysuria and Flank Pain After Lithotripsy: Case 2

After ureteroscopy with lithotripsy, a ureteral stent is often placed to maintain adequate urinary drainage. 10 The stent has one coil that lies in the bladder and another that lies in the renal pelvis. Patients with ureteral stents may experience urinary frequency, urgency, dysuria, flank pain, and hematuria. 10 They may have dull flank pain that becomes sharp with voiding. This phenomenon occurs because the ureteral stent bypasses the normal nonrefluxing uretero-vesical junction, resulting in transmission of pressure to the renal pelvis with voiding. Approximately 80% of patients with a ureteral stent experience stent-related pain that affects their daily activities. 11

POTENTIALLY MISLEADING URINALYSIS

Case 2: dysuria and flank pain after lithotripsy.

A 33-year-old woman with a history of nephrolithiasis presents with a four-week history of urinary frequency, urgency, urge incontinence, and dysuria. She recently had ureteroscopy with lithotripsy of a 9-mm obstructing left ureteral stone; she does not know if a ureteral stent was placed. She has constant dull left flank pain that becomes sharp with voiding. Results of her urinalysis with microscopy are shown in Table 4 .

A. Treat with three days of ciprofloxacin (Cipro), and tailor further antibiotic therapy according to culture results.

B. Treat with 14 days of ciprofloxacin, and tailor further antibiotic therapy according to culture results.

C. Obtain a urine culture and perform plain radiography of the kidneys, ureters, and bladder.

D. Perform a 24-hour urine collection for a metabolic stone workup.

E. Perform computed tomography.

The correct answer is C .

The presence of a ureteral stent causes mucosal irritation and inflammation; thus, findings of leukocyte esterase with white and red blood cells are not diagnostic for urinary tract infection, and a urine culture is required. In this setting, plain radiography of the kidneys, ureters, and bladder would be useful to determine the presence of a stent. If a primary care physician identifies a neglected ureteral stent, prompt urologic referral is indicated for removal. Retained ureteral stents may become encrusted, and resultant stone formation may lead to obstruction. 10

Flank discomfort and recent history of urinary tract manipulation suggest that this is not an uncomplicated urinary tract infection; therefore, a three-day course of antibiotics is inadequate. Although flank pain and urinalysis suggest possible pyelonephritis, this patient should not be treated for simple pyelonephritis in the absence of radiography to identify a stent. A metabolic stone workup may be useful for prevention of future kidney stones, but it is not indicated in the acute setting. Finally, although computed tomography would detect a ureteral stent, it is not preferred over radiography because it exposes the patient to unnecessary radiation. Typically, microscopic hematuria requires follow-up to ensure that there is not an underlying treatable etiology. In this case , the patient's recent ureteroscopy with lithotripsy is likely the etiology.

Urinalysis in a Patient Performing Clean Intermittent Catheterization: Case 3

Case 3: urinalysis in a patient performing clean intermittent catheterization.

A 49-year-old man who has a history of neurogenic bladder due to a spinal cord injury and who performs clean intermittent catheterization visits your clinic for evaluation. He reports that he often has strong-smelling urine, but has no dysuria, urge incontinence, fever, or suprapubic pain. Results of his urinalysis with microscopy are shown in Table 5 .

A. Inform the patient that he has a urinary tract infection, obtain a urine culture, and treat with antibiotics.

B. Refer him to a urologist for evaluation of a complicated urinary tract infection.

C. Perform computed tomography of the abdomen and pelvis to evaluate for kidney or bladder stones.

D. Inform him that no treatment is needed.

E. Obtain a serum creatinine level to evaluate for chronic kidney disease.

The correct answer is D .

Although the urinalysis results are consistent with a urinary tract infection, the clinical history suggests asymptomatic bacteriuria. Asymptomatic bacteriuria is the isolation of bacteria in an appropriately collected urine specimen obtained from a person without symptoms of a urinary tract infection. 12 The presence of bacteria in the urine after prolonged catheterization has been well described; one study of 605 consecutive weekly urine specimens from 20 chronically catheterized patients found that 98% contained high concentrations of bacteria, and 77% were polymicrobial. 13

Similar results have been reported in patients who perform clean intermittent catheterization; another study of 1,413 urine cultures obtained from 407 patients undergoing clean intermittent catheterization found that 50.6% contained bacteria. 14 Guidelines from the Infectious Diseases Society of America recommend against treatment of asymptomatic bacteriuria in nonpregnant patients with spinal cord injury who are undergoing clean intermittent catheterization or in those using a chronic indwelling catheter. 12

In the absence of symptoms of a urinary tract infection or nephrolithiasis, there is no need to culture the urine, treat with antibiotics, refer to a urologist, or perform imaging of the abdomen and pelvis. There is no reason to suspect acute kidney injury in this setting; thus, measurement of the serum creatinine level is also unnecessary.

Data Sources : Literature searches were performed in PubMed using the terms urinalysis review, urinalysis interpretation, microscopic hematuria, CT urogram, urinary crystals, indwelling ureteral stent, asymptomatic bacteriuria, and bacteriuria with catheterization. Guidelines from the American Urological Association were also reviewed. Search dates: October 2012 and June 2013.

Wu X. Urinalysis: a review of methods and procedures. Crit Care Nurs Clin North Am. 2010;22(1):121-128.

Hardy PE. Urinalysis interpretation. Neonatal Netw. 2010;29(1):45-49.

Simerville JA, Maxted WC, Pahira JJ. Urinalysis: a comprehensive review [published correction appears in Am Fam Physician . 2006;74(7):1096]. Am Fam Physician. 2005;71(6):1153-1162.

Cohen RA, Brown RS. Clinical practice. Microscopic hematuria. N Engl J Med. 2003;348(23):2330-2338.

American Urological Association. Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults. http://www.auanet.org/education/asymptomatic-microhematuria.cfm . Accessed June 6, 2014.

Ahmed Z, Lee J. Asymptomatic urinary abnormalities. Hematuria and proteinuria. Med Clin North Am. 1997;81(3):641-652.

Rao PK, Jones JS. How to evaluate ‘dipstick hematuria’: what to do before you refer. Cleve Clin J Med. 2008;75(3):227-233.

Choyke PL. Radiologic evaluation of hematuria: guidelines from the American College of Radiology's Appropriateness Criteria. Am Fam Physician. 2008;78(3):347-352.

Sadow CA, Wheeler SC, Kim J, Ohno-Machado L, Silverman SG. Positive predictive value of CT urography in the evaluation of upper tract urothelial cancer. AJR Am J Roentgenol. 2010;195(5):W337-W343.

Haleblian G, Kijvikai K, de la Rosette J, Preminger G. Ureteral stenting and urinary stone management: a systematic review. J Urol. 2008;179(2):424-430.

Joshi HB, Stainthorpe A, MacDonagh RP, Keeley FX, Timoney AG, Barry MJ. Indwelling ureteral stents: evaluation of symptoms, quality of life and utility. J Urol. 2003;169(3):1065-1069.

Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM Infectious Diseases Society of America; American Society of Nephrology; American Geriatric Society. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults [published correction appears in Clin Infect Dis . 2005;40(10):1556]. Clin Infect Dis. 2005;40(5):643-654.

Warren JW, Tenney JH, Hoopes JM, Muncie HL, Anthony WC. A prospective microbiologic study of bacteriuria in patients with chronic indwelling urethral catheters. J Infect Dis. 1982;146(6):719-723.

Bakke A, Digranes A. Bacteriuria in patients treated with clean intermittent catheterization. Scand J Infect Dis. 1991;23(5):577-582.

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• Published: 04 January 2024

Adult-onset combined methylmalonic acidemia and hyperhomocysteinemia, cblC type with aortic dissection and acute kidney injury: a case report

• Qiufa Hao 1 ,
• Bei Jiang 1 ,
• Yuying Zhao 2 &
• Zhao Hu 1  

BMC Nephrology volume  25 , Article number:  13 ( 2024 ) Cite this article

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Combined methylmalonic acidemia (MMA) and hyperhomocysteinemia, cobalamin C (cblC) type, also named cblC deficiency is a rare autosomal recessive genetic metabolic disease. It progressively causes neurological, hematologic, renal and other system dysfunction. The clinical manifestations are relatively different due to the onset time of disease.

Case presentation

This report describes a rare case of a 26 year old man with cblC deficiency who developed life-threatening aortic dissection and acute kidney injury (AKI) and showed neuropsychiatric symptoms with elevated serum homocysteine and methylmalonic aciduria. After emergent operation and intramuscular cobalamin supplementation therapy, the male recovered from aortic dissection, neurological disorder and AKI. Finally, two previously published compound heterozygous variants, c.482G > A (p.R161Q) and c.658_660del (p.K220del) in the MMACHC gene were detected in this patient and he was confirmed to have cblC deficiency.

Conclusions

Poor cognizance of presenting symptoms and biochemical features of adult onset cblC disease may cause delayed diagnosis and management. This case is the first to depict a case of adult-onset cblC deficiency with aortic dissection. This clinical finding may contribute to the diagnosis of cblC deficiency.

Peer Review reports

Combined methylmalonic acidemia (MMA) and homocystinemia, cobalamin C (cblC) type, also named cblC deficiency is a metabolic disease with errors in vitamin B12 (cobalamin) synthesis [ 1 , 2 ]. The disease is caused by variants of the MMACHC gene and is transmitted as an autosomal recessive trait [ 3 ]. The defect decreases the conversion of vitamin B12 to methylcobalamin and adenosylcobalamin, which will lead to high levels of serum MMA and homocysteine. Adult-onset cblC deficiency usually manifests itself as neuropsychiatric symptoms, progressive cognitive decline, hematological manifestations and renal dysfunction [ 3 ]. The manifestations of cblC deficiency are highly variable and the diagnosis is challenging. However, the prognosis is relatively good with proper treatment. Early diagnosis and treatment are important. Here we describe a case of adult-onset cblC deficiency with aortic dissection and AKI. This is the first study to depict a case of cblC deficiency with aortic dissection as a presenting sign.

A 26-year-old man was admitted to Shandong Provincial Hospital for sudden squeezing chest and abdominal pain for 1 day. On physical examination, his blood pressure was 147/87 mmHg and heart rate was regular at 95 beats pre minute. He was diagnosed with aortic dissection (Stanford type A) and then underwent an operation (Fig.  1 ). Meanwhile, he suffered AKI due to renal artery involvement in aortic dissection and his serum creatinine increased from 180.1 µmol/L to 579.7 µmol/L (62–115 µmol/L) a week later. The operation was successful and his serum creatinine level was maintained at 200–300 µmol/L. Then he was discharged from the hospital. Three months after the operation, he gradually demonstrated anorexia and lost interest in the outside things. Increasingly, he was emotionally unstable and behaved abnormally. He sometimes abused his parents or kept speaking. Then, he went to a doctor in Shandong Provincial Mental Health Center and was diagnosed with a substupor state. His symptoms were partially improved with treatment of olanzapine, sulpiride, and sertraline. Approximately 1.5 months later, his symptoms worsened. He didn’t communicate with others and he had some hallucinations. Then, he was transferred to the neurology department of Qilu hospital. His expression was dim, and his bilateral legs had positiveBabinski and Chadcock signs. Liver and kidney function tests showed serum homocysteine 481.7 µmol/L (< 15 µmol/L) and serum creatinine 326 µmol/L. Antinuclear antibody spectrum, thyroid function, serum ceruloplasmin, blood ammonia and TORCH screen results were normal. Cerebral magnetic resonance imaging and magnetic resonance angiography showed multiple intracranial ischemia areas; multiple cerebral arteriosclerosis and stenosis. To determine the reason for hyperhomocysteinemia, we further examined urinary organic acids by gas-chromatography mass spectrometry and metabolite detection related to carnitine in blood by tandem mass spectrometry. Urinary organic acid analysis showed methylmalonic acid 171.55 mmol/molCr (0.3–3.6 mmol/molCr), 3-hydroxypropionic acid 5.5 mmol/molCr (0.2–1.1 mmol/molCr) and malonic acid 1.31 mmol/molCr (0-0.1 mmol/molCr). The ratio of propionylcarnitine (C3)/free carnitine (C0) in blood was 0.57 (0.02–0.25). The level of vitamin B12 was 1232 pg/ml (243–894 pg/ml). We examined targeted next generation sequencing (NGS) panel in the patient.

.Two compound heterogeneous pathogenic mutations were further identified in the MMACHC gene namely c.482G > A (p. R161Q) and c.658_660del (p. K220del) (Fig.  2 ). The results of NGS panel indicated no suspicious pathogenic genes inducing aortic dissection. These results suggested that the diagnosis was combined MMA and homocystinemia, cblC type. He was treated with hydroxycobalamin, betaine, folinate, L-carnitine and symptomatic treatment for kidney dysfunction. After 4 months, the male had an outpatient visit and his neuropsychiatric symptoms significantly improved. Liver and kidney function tests showed homocysteine 48.7 µmol/L and serum creatinine 141 µmol/L. The urine routine examination showed urinary protein and occult blood is negative.

Images of aortic dissection in the patient before and after the operation. ( A ) Contrast-enhanced CT image of aortic dissection in the aortic arch. ( B ) Contrast-enhanced CT image of aortic dissection in the abdominal aorta. ( C ) CT angiography of aortic dissection on sagittal reconstruction. ( D ) Three-dimensional reconstruction of the aorta demonstrating aortic dissection (Stanford type A). ( E ) CT image of the aortic arch after the operation. (The arrow represents the position of the lesion in the aorta.)

The MMACHC gene mutation sites of the patient. ( A ) The MMACHC gene c.482G > A (p. R161Q). ( B ) The MMACHC gene c.658_660del (p. K220del). (The arrow represents the gene mutation sites.)

Discussion and conclusions

The cblC deficiency is a common type of cobalamin metabolic disorder. The cblC deficiency is the most common type of MMA in China [ 4 ]. The cblC deficiency patients could present anorexia, progressive encephalopathy, renal dysfunction and hematologic abnormalities [ 3 ]. Early diagnosis is very important, which is underscored by gradual progression of the impaired system. The cblC deficiency is triggered by mutation in the MMACHC gene. More than 100 mutations in the MMACHC gene have been reported up to now [ 5 ].In this patient, we found 2 heterozygous mutations: c.482G > A (p. R161Q) and c.658_660del (p. K220del). These 2 mutations have been reported in previous cases [ 6 , 7 ]. The MMACHC gene mutation c.482G > A has been repeatedly reported with late-onset presentation [ 3 ]. Adult-onset cblC deficiency was found the first onset symptoms at the age after 18 years old. In adult-onset cblC deficiency patients, neurological symptoms, isolated psychiatric symptoms and renal involvement are main onset symptoms. With the progress of disease, the manifestations related to neuropathy and cognitive decline are common symptoms. Vascular disease (thromboembolic disease) and renal disease (proteinuria and renal failure) are also found in these patients [ 8 ]. The average level of serum homocysteine at diagnosis was 137.4 µmol/L (27.9–288 µmol/L) [ 8 ]. The level of serum homocysteine in this patient (481.7 µmol/L) was much higher than the average level. The treatment results in adult-onset patients are always with marked improvement. We need to raise awareness for this rare but treatable disease.

The cblC deficiency has been related to neurocognitive and vascular disorders. Thromboembolic complications including recurrent venous thrombosis, pulmonary thrombosis, cor pulmonale and cerebrovascular complications are important conditions in cblC deficiency patients [ 1 ]. Thrombotic microangiopathy and pulmonary arterial hypertension presented in cblC deficiency patients [ 9 , 10 ]. Wide vascular lesions, such as arteriosclerosis, also presented in these patients [ 11 ]. Endothelial dysfunction has been regarded as an important pathogenesis of thrombotic microangiopathy, pulmonary arterial hypertension and arteriosclerosis. To the best of our knowledge, aortic dissection in cblC deficiency patients has not been reported. We may wonder what caused aortic dissection in a young man. The common risk factors of aortic dissection include hypertension, atherosclerosis, congenital diseases, trauma, inflammation, infection and others. The specific risk factors in this patient were male sex and stage 1 hypertension. He was healthy with no drugs previously. The targeted NGS panel indicated no suspicious heritable thoracic aortic diseases inducing aortic dissection. We suspected whether cblC deficiency caused aortic dissection. Hyperhomocysteinemia is a critical biomarker of the cblC deficiency. Epidemiological studies have suggested an association of hyperhomocysteinemia and aortic dissection, but discrepancies exist. It has been proven that hyperhomocysteinemia is a risk factor for arterial endothelial dysfunction [ 12 ]. 48% patients with abdominal aortic aneurysm were found hyperhomocysteinemia and the levels of plasma homocysteine were higher in patients than in control subjects [ 13 ]. In Marfan patients, severe cardiovascular manifestations and aortic dissection were found to be related with homocysteine plasma levels [ 14 ]. In addition, the levels of median plasma homocysteine were higher in patients with spontaneous cervical artery dissection than in control subjects [ 13 ]. Homocysteine plays a significant role in development of aortic dissection and homocysteinemia is a risk factor for aortic dissection. Impaired fibrillin deposition into extracellular matrix was found in aortic aneurysm and dissection. In the FBN1 (the gene for fibrillin-1) mutation patients, reduced fibrillin-1 deposition into pericellular matrix formed weakness of elastic tissue, which could cause aortic aneurysms or dissections. Fibrillin-1 regarded as the important component in extracelluar connective tissue was susceptible to homocysteine attack and irreversible homocysteinylation of long-lived proteins should cause cumulative damage and progressive clinical manifestations [ 13 ]. Moreover, homocysteine could cause premature breakdown in arterial elastic fibers by activating the elastolytic activities [ 13 ]. Thus, we hypothesized that elevated homocysteinemia in this patient was closely associated with aortic dissection.

Renal disease and chronic kidney disease are considerable manifestations of cblC deficiency. Renal complications induced by cblC disease include tubulointerstitial nephritis, thrombotic microangiopathy, hemolytic uremic syndrome and proximal renal tubular acidosis [ 15 , 16 ]. A study reviewed the kidney involvement in adult-onset cblC deficiency patients [ 8 ]. Glomerular disease, renal failure and hemolytic uremic syndrome were commonly found. Kidney biopsies in adult-onset patients usually showed the typical lesions of thrombotic microangiopathy, which was similar with renal damage in infancies with cblC deficies. However, the kidney dysfunction in this case was a process of AKI, caused by aortic dissection. Through symptomatic treatment, his kidney function greatly improved.

In conclusion, we demonstrated a case of cblC deficiency with aortic dissection. This may contribute to the diagnosis of cblC deficiency. It is important to pay more attention to the early diagnosis and treatment of cblC deficiency.

Data Availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Methylmalonic academia

Cobalamin C

• Acute kidney injury

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Department of Nephrology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan, Shandong Province, 250012, China

Qiufa Hao, Bei Jiang & Zhao Hu

Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan, Shandong Province, 250012, China

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Dr. Qiufa Hao was responsible for drafting the manuscript. All authors contributed to taking care of the patient in the hospital. Dr. Yuying Zhao was responsible for final revision and approval of the manuscript.

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Hao, Q., Jiang, B., Zhao, Y. et al. Adult-onset combined methylmalonic acidemia and hyperhomocysteinemia, cblC type with aortic dissection and acute kidney injury: a case report. BMC Nephrol 25 , 13 (2024). https://doi.org/10.1186/s12882-023-03414-9

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• Methylmalonic acidemia
• Hyperhomocysteinemia
• Cobalamin C deficiency
• Aortic Dissection

BMC Nephrology

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Disclosures, abbreviation, response to letter to the editor from wagner et al: “an unusually prolonged case of fgf23-mediated hypophosphatemia secondary to ferric carboxymaltose use”.

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Ipsa Arora, Alison Kaprove, Ronald Perrone, Lisa Ceglia, Response to Letter to the Editor From Wagner et al: “An Unusually Prolonged Case of FGF23-Mediated Hypophosphatemia Secondary to Ferric Carboxymaltose Use”, JCEM Case Reports , Volume 2, Issue 5, May 2024, luae079, https://doi.org/10.1210/jcemcr/luae079

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We thank Wagner et al for their keen interest in our case report ( 1 , 2 ). We appreciate their discussion delving into the intricate understanding of the underlying pathophysiology of hypophosphatemia in patients treated with ferric carboxymaltose (FCM) for iron deficiency anemia. In this letter, we address concerns with our case report raised by Wagner et al.

Our patient's prolonged hypophosphatemia subsequent to FCM administration was predominantly driven by “inappropriately normal FGF23” activity. This assessment was based on persistent hypophosphatemia in the setting of a serum intact FGF23 level of 45 pg/mL (reference range <59 pg/mL) drawn 18 months after FCM administration. The “inappropriately normal PTH” level is not the primary driver of the hypophosphatemia but rather a secondary process due to reduced 1α-hydroxylase activity reducing circulating levels of 1,25-dihydroxyvitamin D and lowering calcium absorption. The rationale for treatment with calcitriol was to raise 1,25-dihydroxyvitamin D, thereby stimulating calcium and phosphate absorption in the gut and reabsorption in the kidney tubules. Via negative feedback, increasing 1,25-dihydroxyvitamin D reduced the parathyroid hormone level as we noted in our patient.

We raised the possibility that the FCM dose was a contributing factor to the prolonged hypophosphatemia in our patient because the dose resulted in markedly elevated ferritin levels lasting over 18 months post infusion. According to a study testing FCM infusions in women of similar age to our patient, the rise in ferritin level post FCM correlated with rises in serum FGF23 level and declines in serum phosphate levels, suggesting that greater rises in ferritin increase risk of FGF23-induced hypophosphatemia ( 3 ).

The contribution of the PKD1 mutation to the prolonged hypophosphatemia is speculative. Although mice with the mutation demonstrate bone loss ( 4 ), there is no evidence that patients with autosomal dominant polycystic kidney disease have low bone mineral density by dual energy x-ray absorptiometry ( 5 , 6 ). We considered the PKD1 mutation because it may play a role in the regulation of FGF23 expression ( 7 ); however, this potential interaction needs additional investigation. The fact that our patient's bone mineral density remained stable over the 3.5 years indicates that treatment with calcitriol successfully prevented significant bone mineral losses.

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Arora   I , Kaprove   A , Perrone   R , Ceglia   L . An unusually prolonged case of FGF23-mediated hypophosphatemia secondary to ferric carboxymaltose use . JCEM Case Rep . 2023 ; 1 ( 5 ): luad117 .

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Wagner   S . Letter to the editor from Wagner et al.: an unusually prolonged case of FGF23 mediated hypophosphatemia secondary to ferric carboxymaltose use . JCEM Case Rep . 2023 .

Wolf   M , Koch   TA , Bregman   DB . Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women . J Bone Miner Res . 2013 ; 28 ( 8 ): 1793 ‐ 1803 .

Spichtig   D , Zhang   H , Mohebbi   N , et al.    Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease . Kidney Int . 2014 ; 85 ( 6 ): 1340 ‐ 1350 .

Evenepoel   P , Claes   K , Cavalier   E , et al.    A distinct bone phenotype in ADPKD patients with end-stage renal disease . Kidney Int . 2019 ; 95 ( 2 ): 412 ‐ 419 .

Zubidat   D , Hanna   C , Randhawa   AK , et al.    Bone health in autosomal dominant polycystic kidney disease (ADPKD) patients after kidney transplantation . Bone Rep . 2023 ; 18 : 101655 .

Grau   L , Gitomer   B , McNair   B , et al.    Interactions between FGF23 and genotype in autosomal dominant polycystic kidney disease . Kidney360 . 2020 ; 1 ( 7 ): 648 ‐ 656 .

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Governor Newsom Unveils Revised State Budget, Prioritizing Balanced Solutions for a Leaner, More Efficient Government

Published: May 10, 2024

The Budget Proposal — Covering Two Years — Cuts Spending, Makes Government Leaner, and Preserves Core Services Without New Taxes on Hardworking Californians

Watch Governor Newsom’s May Revise presentation here

WHAT YOU NEED TO KNOW:  The Governor’s revised budget proposal closes both this year’s remaining $27.6 billion budget shortfall and next year’s projected $28.4 billion deficit while preserving many key services that Californians rely on — including education, housing, health care, and food assistance.

SACRAMENTO – Governor Gavin Newsom today released a May Revision proposal for the 2024-25 fiscal year that ensures the budget is balanced over the next two fiscal years by tightening the state’s belt and stabilizing spending following the tumultuous COVID-19 pandemic, all while preserving key ongoing investments.

Under the Governor’s proposal, the state is projected to achieve a positive operating reserve balance not only in this budget year but also in the next. This “budget year, plus one” proposal is designed to bring longer-term stability to state finances without delay and create an operating surplus in the 2025-26 budget year.

In the years leading up to this May Revision, the Newsom Administration recognized the threats of an uncertain stock market and federal tax deadline delays – setting aside $38 billion in reserves that could be utilized for shortfalls. That has put California in a strong position to maintain fiscal stability.

“Even when revenues were booming, we were preparing for possible downturns by investing in reserves and paying down debts – that’s put us in a position to close budget gaps while protecting core services that Californians depend on. Without raising taxes on Californians, we’re delivering a balanced budget over two years that continues the progress we’ve fought so hard to achieve, from getting folks off the streets to addressing the climate crisis to keeping our communities safe.” – Governor Gavin Newsom

Below are the key takeaways from Governor Newsom’s proposed budget:

A BALANCED BUDGET OVER TWO YEARS.  The Governor is solving two years of budget problems in a single budget, tightening the state’s belt to get the budget back to normal after the tumultuous years of the COVID-19 pandemic. By addressing the shortfall for this budget year — and next year — the Governor is eliminating the 2024-25 deficit and eliminating a projected deficit for the 2025-26 budget year that is $27.6 billion (after taking an early budget action) and $28.4 billion respectively.

CUTTING SPENDING, MAKING GOVERNMENT LEANER.  Governor Newsom’s revised balanced state budget cuts one-time spending by $19.1 billion and ongoing spending by $13.7 billion through 2025-26. This includes a nearly 8% cut to state operations and a targeted elimination of 10,000 unfilled state positions, improving government efficiency and reducing non-essential spending — without raising taxes on individuals or proposing state worker furloughs. The budget makes California government more efficient, leaner, and modern — saving costs by streamlining procurement, cutting bureaucratic red tape, and reducing redundancies.

PRESERVING CORE SERVICES & SAFETY NETS.  The budget maintains service levels for key housing, food, health care, and other assistance programs that Californians rely on while addressing the deficit by pausing the expansion of certain programs and decreasing numerous recent one-time and ongoing investments.

NO NEW TAXES & MORE RAINY DAY SAVINGS.  Governor Newsom is balancing the budget by getting state spending under control — cutting costs, not proposing new taxes on hardworking Californians and small businesses — and reducing the reliance on the state’s “Rainy Day” reserves this year.

HOW WE GOT HERE:  California’s budget shortfall is rooted in two separate but related developments over the past two years.

• First, the state’s revenue, heavily reliant on personal income taxes including capital gains, surged in 2021 due to a robust stock market but plummeted in 2022 following a market downturn. While the market bounced back by late 2023, the state continued to collect less tax revenue than projected in part due to something called “capital loss carryover,” which allows losses from previous years to reduce how much an individual is taxed.
• Second, the IRS extended the tax filing deadline for most California taxpayers in 2023 following severe winter storms, delaying the revelation of reduced tax receipts. When these receipts were able to eventually be processed, they were 22% below expectations. Without the filing delay, the revenue drop would have been incorporated into last year’s budget and the shortfall this year would be significantly smaller.

CALIFORNIA’S ECONOMY REMAINS STRONG:  The Governor’s revised balanced budget sets the state up for continued economic success. California’s economy remains the 5th largest economy in the world and for the first time in years, the state’s population is increasing and tourism spending recently experienced a record high. California is #1 in the nation for new business starts , #1 for access to venture capital funding , and the #1 state for manufacturing , high-tech , and agriculture .

Additional details on the May Revise proposal can be found in this fact sheet and at www.ebudget.ca.gov .

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Musculoskeletal Research Center Overview

The Washington University Musculoskeletal Research Center (MRC) was formally established in 2009 as the home for Washington University researchers interested in musculoskeletal biology and medicine. The Center is administered by a partnership between the Departments of Orthopaedic Surgery and Internal Medicine, Division of Bone and Mineral Diseases. 

The main goals of the MRC are to:

• support and enhance research on the musculoskeletal system
• foster collaborations within its research community
• mentor early-stage investigators and attract investigators from other disciplines
• train the next generation of musculoskeletal investigators

Two grants provide support for the infrastructure and training missions of the MRC, the Resource Based Center for Musculoskeletal Biology and Medicine (RCMBM, P30 AR074992), directed by Dr. Matthew Silva; and the Skeletal Disorders Training Program (SDTP, T32 AR060719), directed by Dr. Roberto Civitelli.  Additional support is provided by the Departments of Orthopaedic Surgery and Internal Medicine, and by the Dean of the Medical School.

Our Research Community currently consists of 96 investigators. There are 84 Washington University faculty from 15 Departments:  Biomedical Engineering, Cell Biology & Physiology, Developmental Biology, Internal Medicine (Divisions of Bone & Mineral Diseases, Cardiology, Geriatrics & Nutritional Science, Infectious Diseases, Oncology, Nephrology, and Rheumatology), Mechanical Engineering, Neurology, Neuroscience, Neurosurgery, Orthopaedic Surgery, Pathology and Immunology, Pediatrics, Program in Physical Therapy, Radiation Oncology, Radiology, and Surgery. In addition, there are 12 Affiliate Members from six non-WashU institutions:  Saint Louis University, Univ. Missouri-Columbia, Ohio State Univ., Univ. Illinois-Urbana Champaign, Univ. Nebraska, and Univ. Virginia.

The MRC operates through four main activity areas:

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Core A – Administration  

Provides the overall leadership and management of the Research Core Facilities, integrates Core Center Components and Activities; communicates with stake holders (Newsletter, Website, Twitter/X, LinkedIn); coordinates Core Center Activities with other WashU Programs.

Core B – Musculoskeletal Structure and Strength

Provides critical support to members of the Research Base to enable rigorous utilization of methods to quantify morphology and mechanical properties from musculoskeletal tissues (bone, tendon, muscle, disc).  Services include x-ray based skeletal imaging and biomechanical testing.

Core C – Musculoskeletal Histology and Morphometry

Provides histological services for the identification and analysis of molecular phenotypes of our target tissues, bone, cartilage, disc, muscle, tendon and ligament, in developing and adult mice. Services include preparation of tissues and tissue sections (paraffin, frozen, plastic); specialized staining for musculoskeletal tissues; training in the techniques of sectioning, immunohistochemistry, RNA in situ hybridization and histomorphometry. Confocal microscopy is also supported.

Core D –  Animal Models of Bone and Joint Injury & Disease

Supports the generation of models and reagents to study fracture healing, osteoarthritis and rheumatoid arthritis in mice. These include models for physical and surgical knee injury, and models to induce inflammation, as well as repository of joint tissues and reagents to induce systemic inflammation (RA models). Supports the evaluation of functional outcomes in mice using measures of in vivo behavior and pain.

2. Training and Education

The MRC offers a variety of educational opportunities for graduate students, post-doctoral trainees and faculty interested in musculoskeletal research.  These include lectures, namely, the Skeletal Biology and Pathophysiology Mini-Course , focused on didactic lectures on the normal and pathobiology of the musculoskeletal system; Summer Educational Seminars , focused on technologies available in the MRC, their application and data interpretation; and workshops focused on Rigor and Reproducibility .

The Institutional SDTP (T32) offers mentored research training for 3 graduate students and 3 post-doctoral fellows each year in five areas of musculoskeletal research: Musculoskeletal Biomechanics, Skeletal Development and Regeneration, The Skeleton and Other Systems, Skeletal Immunology , and Tumor-Skeleton Interactions .  Trainees can draw from an interdisciplinary pool of 28 mentors, representing 9 Departments and Programs at Washington University, all members of the MRC Research Community.

3. Enrichment Program

In addition to the annual Musculoskeletal Symposium , one major research seminar series and two journal clubs/discussion groups are also organized under the aegis of the MRC.  The weekly Avioli Musculoskeletal Research Seminars represent the main venue for new research by MRC faculty members and senior trainees, as well as invited guest speakers.  Journal clubs are focused on complementary research areas pertinent to the musculoskeletal system; including the Experimental Skeletal Biology Journal Club/Data Club , led by Dr. Veis; and the Mechanobiology Journal Club , organized by Dr. Tang. Opportunities for clinical education are numerous, via the weekly Skeletal Health Multidisciplinary Case Conference  and Orthopedic Grand Rounds and Core Lectures . 

4. Development Program

This program consists of initiatives aimed at fostering new research directions by MRC investigators; reaching out to and attracting investigators from other disciplines; providing support for trainees as they transition to independence; and facilitating the translation of basic findings to clinical research. 

The MRC funds three Pilot & Feasibility Grants per year ($40,000/yr for 1-2 years).  The scope of this grant program is to support new investigators without major independent funding; or established investigators in other fields committing their skills to musculoskeletal research; or established musculoskeletal investigators embarking in a new direction in our discipline; or post-doctoral fellow as they transition to independence. One of the P&F grants each year is supported by a gift of the Lottie C. Hardy Charitable Trust.

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Nephrology Case Conference

Oct 16, 2014

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Nephrology Case Conference. 報告日期 : 2011/10/05 指導老師 : 方基存教授 報告醫師 : R3 陳惠湘. Side effects of antiviral treatment. HCV Treatment in CKD patient. HCV and CKD. Review the case. Case Presentation. Discussion. Outlines. Case Presentation.

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Nephrology Case Conference 報告日期: 2011/10/05 指導老師: 方基存教授 報告醫師: R3 陳惠湘

Side effects of antiviral treatment HCV Treatment in CKD patient HCV and CKD Review the case Case Presentation Discussion Outlines Company Logo

Case Presentation

Patient Profiles • Name: 徐O緯 • Gender: Male • Birthday: 1954/08/25 (57y/o) • Ethnic: Taiwanese • Occupation: sales, retired • Marital status: married • Traveling history: nil • Admission during 2011/04/23~2011/04/29 at GI ward Company Logo

Chief Complaint • Progressive depressive mood and behavior change since about one month ago Company Logo

Present Illness -1 • This 57 y/o male patient is a case with histories of ESRD under regular HD and HCV carrier who follow up at our GI OPD. • Since one month before admission, he was noted with agitation, depressive mood, insomnia and suicide ideation. • According to his wife, he has received Interferon + Ribavirin treatment for hepatitis C since about one and half month ago. Company Logo

Present Illness -2 • He denied constipation and high protein diet. No bloody or tarry stool noted, no fever checked. • No other medication taken except those from OPD. • General malaise but no focal limb weakness. Company Logo

Past history • End stage renal disease under regular hemodialysis via left AVG for about 13 years • Hepatitis C carrier • Known when screening for HD • History of tooth retraction with bleeding, blood transfusion(+) • Secondary hyperparathyroidism status post total parathyroidectomy with autotransplantation in 2008 • Nephrolithiasis • Hypertension known for 13 years Company Logo

Personal history • Allergy: no known allergy history • Smoking: denied • Alcohol: denied • Betel nut: denied Company Logo

Family history • Family history: Colon cancer GN Company Logo

Physical Examination -1 • Vital signs: • BT:36.3’C, BP:120/82mmHg, HR:75/min, RR:16/min • General appearance: chronic ill looking • Consciousness: oriented, E4V5M6 • HEENT: • Conjunctiva: pale, Sclera: anicteric • Neck: no stiffness, no lymphadenopathy • Chest: • Smooth respiratory pattern • Breathing sound: bilateral coarse • Heart sound: regular heart beat, murmur(-) Company Logo

Physical Examination -2 • Abdomen: • soft, no tenderness • normoactive bowel sound • Bruit(?) • Extremities • Freely movable • No pitting edema • Left AVG bruit/thrill(?) • Skin: • Intact, no rashes Company Logo

Lab data when admitted (4/22-4/23) • Leukopenia with lymphopenia • Thrombocytopenia • Normocytic anemia Company Logo

Lab data when admitted (4/22-4/23)  68 (4/23)  68 (4/25) Company Logo

CXR (4/22) • No definite active lung lesion Company Logo

Brain CT (4/22) • No definite evidence of infarction Company Logo

Current medications at OPD • 2011/2/15 Nephrology OPD: • Fosinopril(10mg) 0.5# QD • Silymarin(150mg) 1# QD • Carvedilol(6.25mg) 0.5# QD • 2011/4/11 GI OPD • Ribavirin(200mg) 1# QD • Peginterferon alfa-2b(100mcg) 1pc QW • Mefenamic acid(250mg) 1# QID • 2011/04/20 HD room • Epoetin beta (2000iu) 1pc TIW • Atenolol(100mg) 1# QD Company Logo

Impression • Suspect Interferon induced mood disorder • Leukopenia/Thrombocytopenia and Anemia, suspect Interferon/Ribavirin related • ESRD under hemodialysis • HCV carrier • Secondary hyperparathyroidism status post total parathyroidectomy with autotransplantation • Nephrolithiasis Company Logo

Admission course -1 c/s Psychi doctor 1st suicide at ER 2nd suicide at ward Hold IFN+RBV since 4/22 (s/p 6th injection) Company Logo

Admission course -2 Company Logo

Review this patient’s history HCV-RNA 0.006 million IU/ml HCV-RNA 15.2 million IU/ml HCV-RNA (-) HCV-RNA (-) HBV(-) Genotype 1b PegIFN 100mcg/QW P’t want to withdraw the Tx… RBV 200mg 3#BID RBV 200mg 1#QD EPO 2000iu TIW 5000 Company Logo

HCV and CKD

Epidemiology of HCV • Hepatitis C virus is a blood-borne pathogen that appears to be endemic in most parts of the world. • WHO estimates that the global prevalence of HCV infection averages 3%, or around 170 million infected persons worldwide. World J Gastroenterol 2007 May 7; 13(17): 2436-2441 Company Logo

Epidemiology of HCV in CKD P’t -1 • The reported prevalence of HCV infection in haemodialysis units of developed countries has ranged from 2.6-22.9% (with a mean of 13.5%) • But prevalence may be as high as 70% in developing countries. Postgrad Med J 2010;86:486-492 Company Logo

Epidemiology of HCV in CKD P’t -2 • High rate of HCV transmission among CKD patients • direct exposure to infectious blood and/or blood products because of inadequate infection control. • improving since 1992 with regular screening • Cross contamination between patients can occur in dialysis units • lack of disinfection of commonly utilised medication equipment and supplies • the use of shared vials of heparin • blood spills which are not immediately cleaned Postgrad Med J 2010;86:486-492 Company Logo

Natural history of HCV in CKD P’t -1 • ALT values may not be a useful indicator of liver damage among CKD patients • Suppression of ALT synthesis in hepatocytes, inhibition of its release into the bloodstream and accelerated clearance from serum have been proposed as probable mechanisms of low ALT values in CKD patients • Liver biopsy may be required for CKD patients to assess the degree of liver damage and to plan antiviral therapy. • Transjugular biopsy • Elastography Postgrad Med J 2010;86:486-492 Company Logo

Natural history of HCV in CKD P’t -2 • In renal transplant patient • renal transplant recipients with HCV infection had higher mortality rates (RR 2.23) • graft losses were higher (RR 1.96) • Risk for development of post-transplant diabetes mellitus and MGN was also higher Postgrad Med J 2010;86:486-492 Company Logo

HCV vs. CKD • Chronic infection with hepatitis C could be both the main cause and the complication of CKD. • Probable association between HCV infection and renal disease was first reported in 1990.  Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 1990;162:569-70 Company Logo

HCV vs. CKD -- associated • Study Design: National cohort study. • Setting & Participants: HCV-infected and -uninfected veterans in ERCHIVES (Electronically Retrieved Cohort of HCV Infected Veterans) in 2001-2006. • Outcomes: Incident CKD stages 3-5. • Conclusions: HCV infection is associated with higher risk and shorter time to CKD despite having a lower prevalence of many CKD risk factors. HCV-infected persons should have targeted monitoring for the development and progression of CKD. Company Logo

HCV vs. CKD -- associated Company Logo

HCV vs. CKD -- associated • Study Design: Cross-sectional study. • Setting & Participants: A large-scale community study with 54,966 adults in a Taiwanese county endemic for HBV and HCV infection. • Conclusions: HCV infection, but not HBV infection, was associated significantly with prevalence and disease severity of CKD in this HBV and HCV endemic area Company Logo

HCV vs. CKD -- not associated • METHODS: We conducted a cohort study of 167,569 patients included in a national health care claims database from January 1, 2003–December 31, 2006, with a mean follow-up of 25.3 months. We used multivariable logistic regression analyses to measure the independent effect of HCV status on the baseline prevalence of and progression to CKD • CONCLUSIONS: We found no association between HCV and risk of development of CKD. Company Logo

HCV vs. CKD – not associated Company Logo

Mechanism and Pathogenesis of HCV induced renal injury -1 Hepat Mon. 2010; 10(4): 258-269 Company Logo

Mechanism and Pathogenesis of HCV induced renal injury -2 Company Logo

Mechanism and Pathogenesis of HCV induced renal injury -4 Hepat Mon. 2010; 10(4): 258-269 Company Logo

Mechanism and Pathogenesis of HCV induced renal injury -5 • Mixed cryoglobulinemia induced GN • The most documented extrahepatic manifestation of hepatitis C virus (HCV) infection is mixed cryoglobulinemia (MC). • MC is characterised by the presence of temperature-sensitive protein complexes • precipitates when the serum is incubated at a temperature lower than 37C. • in type II MC, cryoglobulins are composed of a monoclonal rheumatoid factor (usually, IgMk) against polyclonal IgG Lupus (2000) 9, 83±91 Company Logo

Mechanism and Pathogenesis of HCV induced renal injury -6 Lupus (2000) 9, 83±91 Company Logo

Mechanism and Pathogenesis of HCV induced renal injury -7 Nephrol Dial Transplant (2007) 22: 1840–1848 Company Logo

Mechanism and Pathogenesis of HCV induced renal injury -8 (B) Non-cryoglobulinaemic membranoproliferative glomerulonephritis (C) Membranous nephropathy (D) Focal and segmental sclerosis (E) Amyloidosis (F) Fibrillary glomerulonephritis. (G) Post-transplant thrombotic microangiopathy (H) Transplant glomerulopathy Company Logo

Treatment of HCV in CKD Patients

Antiviral therapy -- Interferon • Interferons are an important part of the innate antiviral immune response. • They induce interferon-stimulated genes (ISGs) that help establish an antiviral state within cells • Act by binding to cell surface receptors, activating a response cascade that culminates in the expression of multiple ISGs, some of which block viral protein synthesis. In addition, it may lead to a decrease in viral RNA stability. Company Logo

Antiviral therapy -- Interferon • Alpha interferons also interact with the adaptive immune system. • It promote the proliferation of memory T-cells, prevent T-cell apoptosis, stimulate natural killer cell activation, and stimulate dendritic cell maturation. • It also upregulate the production of major histocompatibility complex class-I and class-II peptides and may promote a T-helper-1 phenotype over a T-helper-2 phenotype. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 2005; 436:967. Company Logo

Antiviral therapy -- PEG-Interferon • The attachment of polyethylene glycol to a protein (pegylation) reduces its rate of absorption following subcutaneous injection, reduces renal and cellular clearance, and decreases the immunogenicity of the protein. • All of these effects tend to enhance the half-life of the pegylated versus the native protein. • On the other hand, pegylation may interfere with the ability of a protein to bind to its receptor, thereby decreasing its biologic effect. Thus, the true biologic effect of the pegylated protein is determined by the balance of these competing properties • Two formulations of peginterferon alfa have been developed: peginterferon alfa-2a (Pegasys, Roche Pharmaceuticals), and peginterferon alfa-2b (Peg-Intron, Schering-Plough Corporation).  Immunogenicity of recombinant IL-2 modified by covalent attachment of polyethylene glycol. J Immunol 1990; 144:209 Company Logo

Antiviral therapy -- Ribavirin • Ribavirin is a nucleoside analog which has a broad spectrum of antiviral activity • It inhibits the replication of RNAviruses in cell culture. Ribavirin appears to decrease hepatitis C virus infectivity in a dose-dependent manner • Several mechanisms may be involved: • Depletion of intracellular triphosphate pools through direct inhibition of inosine monophosphate dehydrogenase • Inhibition of the 5'-cap structure of viral mRNA • Inhibition of the viral-dependent RNA polymerases • Altering the balance between proinflammatory (Th1-like) and antiinflammatory (Th2-like) cytokines • Inducing mutations into viral RNA • Potentiating interferon action  Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature 2004; 432:922 Company Logo

Treatment of HCV -1 HEPATOLOGY, Vol. 49, No. 4, 2009 Company Logo

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State rests case in Elizabeth Fox-Doerr murder trial after week-long presentation to jurors

E VANSVILLE — The prosecution on Monday afternoon rested its case against Elizabeth Fox-Doerr, who is standing trial for the 2019 killing of her husband, veteran Evansville firefighter Robert F. Doerr II.

Prosecutor Stan Levco, who is trying the case alongside Vanderburgh County's elected prosecutor, Diana Moers, rested after presenting jurors with hours of Fox-Doerr's taped police interrogation and portions of her testimony to a grand jury.

Now, Fox-Doerr's legal counsel is preparing to present its own evidence and witness testimony to jurors beginning Tuesday as they seek to refute allegations that Fox-Doerr, 52, conspired with her alleged lover, convicted murderer Larry Richmond Sr., to ambush and kill her husband.

According to court records, Fox-Doerr has pleaded not guilty to charges of aiding, inducing, or causing murder and conspiracy to commit murder, both of which are Level 1 felonies, for that alleged murder-conspiracy plot.

Richmond, 46, is scheduled to stand trial in August. He did not testify as a state witness at Fox-Doerr's trial.

Prosecutors contend that Richmond shot and killed Doerr, 51, outside the home he shared with his wife on Feb. 26, 2019, with a powerful Taurus Judge revolver that fired a mix of standard pistol ammunition and shotgun-like projectiles.

The Vanderburgh County Coroner's Office pronounced Doerr dead at the scene. Doerr served with the Evansville Fire Department for 28 years , and has been described by his colleagues and the Evansville Police Department as a consummate professional and "hero."

According to records entered into evidence last week, Richmond called Fox-Doerr about 15 minutes prior to the shooting — a call Fox-Doerr deleted from her cellphone's hard drive and hid from investigators until she was confronted during a heated, hours-long police interrogation.

Levco and Moers held off on presenting footage of the interrogation to jurors until Monday morning. In that footage, jurors heard Fox-Doerr repeatedly tell detectives that she could not think of any phone calls that she had failed to mention to police in the immediate aftermath of Doerr's killing.

But when confronted with official records from her cell phone provider that showed Richmond had called her the night of the shooting, Fox-Doerr ultimately admitted that Richmond had, in fact, called her and that they spoke for about five minutes.

"(You said) nothing about any calling until we pulled it out of you," a detective told Fox-Doerr.

"I didn't tell anybody to hurt my husband!" Fox-Doerr shouted in reply. She went on to claim that Richmond had called to ask what she and Doerr planned to do that weekend. Fox-Doerr repeatedly denied ever having discussed a murder plot with Richmond.

"It makes it look like I did it when I didn't," Fox-Doerr later told detectives.

Former FBI Task Force Officer Jeff Hands conducted portions of the interrogation that jurors reviewed Monday. Under cross examination from Fox-Doerr's lead attorney, Mark Phillips, Hands admitted that he had not reviewed any evidence or witness testimony that could show Fox-Doerr had spoken with Richmond about committing a murder.

"You're not aware of 'Becky' (Fox-Doerr) talking to anyone about killing anybody, correct?" Phillips asked Hands.

"Yes," Hands replied.

Hands' answer to Phillips' question points to the circumstantial nature of the state's case against Fox-Doerr.

Prosecutors and Fox-Doerr are in agreement that she deleted the phone call from Richmond. But investigators have not been able to obtain a conclusive account of what the two spoke about.

Vanderburgh County Superior Court Judge Robert Pigman adjourned Monday's proceedings just before 4:30 p.m., with Levco informing the judge immediately thereafter that the state would rest its case.

Phillips told the Courier & Press Fox-Doerr would present a defense to jurors beginning Tuesday. When the defense rests its case, both sides will present their closing arguments before jurors begin deliberations.

This article originally appeared on Evansville Courier & Press: State rests case in Elizabeth Fox-Doerr murder trial after week-long presentation to jurors

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Star witness Michael Cohen says Trump was intimately involved in all aspects of hush money scheme

The jury in Donald Trump’s hush money trial heard an audio recording Monday that Michael Cohen secretly made of himself briefing Trump in September 2016 about a plan to buy the rights to ex-Playboy model Karen McDougal’s story from the National Enquirer.

The fourth week of witness testimony in Donald Trump’s hush money trial could be a doozy: Michael Cohen, the prosecution’s star witness, has taken the stand. (AP video by Joe Frederick)(AP produced by Javier Arciga)

Donald Trump’s fixer-turned-foe, Michael Cohen, is directly implicating the former president in a hush money scheme. The AP’s Mike Sisak explains.

Assistant district attorney Susan Hoffinger, center, questions witness Michael Cohen, far right, as Donald Trump, far left, looks on in Manhattan criminal court, Monday, May 13, 2024, in New York. (Elizabeth Williams via AP)

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Michael Cohen, left, testifies on the witness stand in Manhattan criminal court, Monday, May 13, 2024, in New York. (Elizabeth Williams via AP)

Michael Cohen testifies on the witness stand with a National Enquirer cover story about Donald Trump displayed on a screen in Manhattan criminal court, Monday, May 13, 2024, in New York. (Elizabeth Williams via AP)

Former President Donald Trump reacts as Michael Cohen testified that he told Trump that the Stormy Daniels story was not contained. in Manhattan criminal court, Monday, May 13, 2024, in New York. (Elizabeth Williams via AP)

Michael Cohen leaves his apartment building on his way to Manhattan criminal court, Monday, May 13, 2024, in New York. (AP Photo/Julia Nikhinson)

Michael Cohen, former attorney to Donald Trump, leaves the District Attorney’s office in New York, March 13, 2023. (AP Photo/Yuki Iwamura, File)

Former President Donald Trump returns to the courtroom after a break at Manhattan criminal court, Monday, May 13, 2024, in New York. (AP Photo/Seth Wenig, Pool)

Republican presidential candidate and former President Donald Trump attends his trial at Manhattan Criminal Court in New York on Monday, May 13 2024. (Steven Hirsch/New York Post via AP, Pool)

Former President Donald Trump and lawyer Todd Blanche return to his criminal trial after a short break at Manhattan criminal court, Monday, May 13, 2024, in New York. (Sarah Yenesel/Pool Photo via AP)

Republican presidential candidate, former President Donald Trump attends his trial at Manhattan Criminal Court in New York on Monday, May 13, 2024. (Steven Hirsch/New York Post via AP, Pool)

Former President Donald Trump sits in Manhattan criminal court, Monday, May 13, 2024, in New York. (Mark Peterson/New York Magazine via AP, Pool)

Former President Donald Trump sits in the courtroom at Manhattan criminal court, Monday, May 13, 2024, in New York. (Mark Peterson/New York Magazine via AP, Pool)

NEW YORK (AP) — Donald Trump was intimately involved with all aspects of a scheme to stifle stories about sex that threatened to torpedo his 2016 campaign, his former lawyer said Monday in matter-of-fact testimony that went to the heart of the former president’s hush money trial .

“Everything required Mr. Trump’s sign-off,” said Michael Cohen, Trump’s fixer-turned-foe and the prosecution’s star witness in a case now entering its final, pivotal stretch.

In hours of highly anticipated testimony, Cohen placed Trump at the center of the hush money plot, saying the then-candidate had promised to reimburse the lawyer for the money he fronted and was constantly updated about behind-the-scenes efforts to bury stories feared to be harmful to the campaign.

What to know about Trump’s hush money trial:

• Follow the AP’s live coverage as Trump’s former lawyer returns to the stand.
• A guide to terms used in the Trump trial.
• Trump is the first ex-president on criminal trial. Here’s what to know about the hush money case.
• Trump is facing four criminal indictments, and a civil lawsuit. You can track all of the cases here.

“We need to stop this from getting out,” Cohen quoted Trump as telling him in reference to porn actor Stormy Daniels’ account of a sexual encounter with Trump a decade earlier. The then-candidate was especially anxious about how the story would affect his standing with female voters.

A similar episode occurred when Cohen alerted Trump that a Playboy model was alleging that she and Trump had an extramarital affair. “Make sure it doesn’t get released,” was Cohen’s message to Trump, the lawyer said. The woman, Karen McDougal, was paid $150,000 in an arrangement that was made after Trump received a “complete and total update on everything that transpired.”

Former President Donald Trump, with attorney Todd Blanche, right, arrives at Manhattan criminal court in New York, on Friday, May 10, 2024. (Timothy A. Clary/Pool Photo via AP)

“What I was doing, I was doing at the direction of and benefit of Mr. Trump,” Cohen testified.

Trump has pleaded not guilty and denied having sexual encounters with the two women.

Cohen is by far the prosecution’s most important witness, and though his testimony lacked the electricity that defined Daniels’ turn on the stand last week, he nonetheless linked Trump directly to the payments and helped illuminate some of the drier evidence such as text messages and phone logs that jurors had previously seen.

The testimony of a witness with such intimate knowledge of Trump’s activities could heighten the legal exposure of the presumptive Republican presidential nominee if jurors deem him sufficiently credible. But prosecutors’ reliance on a witness with such a checkered past — Cohen pleaded guilty to federal charges related to the payments — also carries sizable risks with a jury and could be a boon to Trump politically as he fundraises off his legal woes and paints the case as the product of a tainted criminal justice system.

The men, once so close that Cohen boasted that he would “take a bullet” for Trump, had no visible interaction inside the courtroom. The sedate atmosphere was a marked contrast from their last courtroom faceoff, when Trump walked out of the courtroom in October after his lawyer finished questioning Cohen during his civil fraud trial.

This time around, Trump sat at the defense table with his eyes closed for long stretches of testimony as Cohen recounted his decade-long career as a senior Trump Organization executive, doing work that by his own admission sometimes involved lying and bullying others on his boss’s behalf.

Jurors had previously heard from others about the tabloid industry practice of “catch-and-kill,” in which rights to a story are purchased so that it can then be quashed. But Cohen’s testimony, which continues Tuesday, is crucial to prosecutors because of his direct communication with the then-candidate about embarrassing stories he was scrambling to suppress.

Cohen also matters because the reimbursements he received from a $130,000 hush money payment to Daniels, which prosecutors say was meant to buy her silence in advance of the election, form the basis of 34 felony counts charging Trump with falsifying business records. Prosecutors say the reimbursements were logged, falsely, as legal expenses to conceal the payments’ true purpose. Defense lawyers say the payments to Cohen were properly categorized as legal expenses.

Under questioning from a prosecutor, Cohen detailed the steps he took to mask the payments. When he opened a bank account to pay Daniels, an action he said he told Trump he was taking, he told the bank it was for a new limited liability corporation but withheld the actual purpose.

“I’m not sure they would’ve opened it,” he said, if they knew it was ”to pay off an adult film star for a nondisclosure agreement.”

To establish Trump’s familiarity with the payments, Cohen told the jury that Trump had promised to reimburse him. The two men even discussed with Allen Weisselberg, a former Trump Organization chief financial officer , how the reimbursements would be paid as legal services over monthly installments, Cohen testified.

Republican presidential candidate former President Donald Trump speaks during his campaign rally in Wildwood, N.J., Saturday, May 11, 2024. (AP Photo/Matt Rourke)

And though Trump’s lawyers have said he acted to protect his family from salacious stories, Cohen described Trump as preoccupied instead by the impact they would have on the campaign.

He said Trump even sought to delay finalizing the Daniels transaction until after Election Day so he wouldn’t have to pay her.

“Because,” Cohen testified, “after the election it wouldn’t matter” to Trump.

Cohen also gave jurors an insider account of his negotiations with David Pecker , the then-publisher of the National Enquirer, who was such a close Trump ally that Pecker told Cohen his publication maintained a “file drawer or a locked drawer” where files related to Trump were kept.

That effort took on added urgency following the October 2016 disclosure of an “Access Hollywood” recording in which Trump was heard boasting about grabbing women sexually.

The Daniels payment was finalized several weeks after that revelation, but Monday’s testimony also centered on a deal earlier that fall with McDougal.

Cohen testified that he went to Trump immediately after the National Enquirer alerted him to a story about the alleged McDougal affair. “Make sure it doesn’t get released,” he said Trump told him.

AP AUDIO: Trump fixer-turned-foe, Michael Cohen, says in hush money trial he lied, bullied on boss’s behalf

AP correspondent Eric Tucker reports Michael Cohen is really important to the hush money case against Donald Trump.

Trump checked in with Pecker about the matter, asking him how “things were going” with it, Cohen said. Pecker responded, ‘We have this under control, and we’ll take care of this,” Cohen testified.

Cohen also said he was with Trump as Trump spoke to Pecker on a speakerphone in his Trump Tower office.

“David had stated that it’s going to cost them $150,000 to control the story,” Cohen said. He quoted Trump as saying: “No problem, I will take care of it,” which Cohen interpreted to mean that the payment would be reimbursed.

To lay the foundation that the deals were done with Trump’s endorsement, prosecutors elicited testimony from Cohen designed to show Trump as a hands-on manager. Acting on Trump’s behalf, Cohen said, he sometimes lied and bullied others, including reporters.

“When he would task you with something, he would then say, ‘Keep me informed. Let me know what’s going on,’” Cohen testified. He said that was especially true “if there was a matter that was troubling to him.”

Defense lawyers have teed up a bruising cross-examination of Cohen, telling jurors during opening statements that he’s an “admitted liar” with an “obsession to get President Trump.”

Prosecutors aim to blunt those attacks by acknowledging Cohen’s past crimes to jurors and by relying on other witnesses whose accounts, they hope, will buttress Cohen’s testimony. They include a lawyer who negotiated the hush money payments on behalf of Daniels and McDougal, as well as Pecker and Daniels.

After Cohen’s home and office were raided by the FBI in 2018, Trump showered him with affection on social media and predicted that Cohen would not “flip.” Months later, Cohen did exactly that, pleading guilty to federal campaign-finance charges.

Besides pleading guilty to the hush money payments, Cohen later admitted lying to Congress about a Moscow real estate project that he had pursued on Trump’s behalf during the heat of the 2016 campaign. He was sentenced to three years in prison, but spent much of it in home confinement.