Vitamin A deficiency associated with urinary retinol binding protein wasting in Dent’s disease

Background

Three patients with Dent’s disease presented with complaints of impaired night vision or xerophthalmia and were found to have severely decreased serum retinol concentrations. Retinol, bound to its carrier retinol-binding protein (RBP), is filtered at the glomerulus and reabsorbed at the proximal tubule. We hypothesized that urinary loss of retinol-RBP complex is responsible for decreased serum retinol.

Objective and methods

The study aim was to investigate vitamin A status and RBP in serum and urine of patients with genetically confirmed Dent’s disease.

Results

Eight patients were studied, three boys had clinical vitamin A deficiency, three had asymptomatic deficiency, and two young men with Dent’s disease and impaired renal function had normal retinol values. Serum RBP concentrations were low in patients with vitamin A deficiency and were correlated with vitamin A levels. Urinary RBP concentrations were increased in all patients (2,000-fold), regardless of vitamin A status. This was in contrast to patients with glomerular proteinuria who had only mildly increased urinary RBP with normal serum RBP and vitamin A, and patients with cystinosis with impaired renal function who had massive urinary RBP losses but without a decrease in serum RBP or vitamin A levels. Treatment with vitamin A supplements in patients with retinol deficiency resulted in rapid resolution of ocular symptoms and an increase in serum retinol concentrations.

Conclusions

Vitamin A deficiency is common in patients with Dent's disease and preserved renal function. We therefore recommend screening these patients for retinol deficiency and treating them before visual symptoms develop.     

Phenotype and genotype of Dent’s disease in three Korean boys

Dents disease is a hereditary renal tubular disorder caused by mutations of the CLCN5 gene and is clinically characterized by low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. This disease has been reported in several countries. However, there are some phenotypic differences between countries, such as hypophosphatemic rickets, progressive renal failure and hematuria. In this study, phenotypes were analyzed in three Korean boys with Dents disease, and genetic diagnoses were performed using a new convenient method using peripheral blood RNA. Gene studies revealed two nonsense mutations, R637X in two patients and E609X in one patient. The phenotypes of the two patients with R637X were very similar to those of Japanese patients, i.e., they presented with asymptomatic proteinuria without rickets, renal failure or hematuria. The E609X patient was diagnosed genetically at 3 months of age before the onset of clinical symptoms because of superimposed furosemide-induced nephrolithiasis. This is the first report to characterize mutations in the CLCN5 gene in Korean patients with Dents disease, and expands the spectrum of CLCN5 mutations by reporting a novel mutation, E609X. In addition, the mutational analysis using peripheral blood RNA can be easily applied in the clinical diagnosis.     

Family history may be misleading in the diagnosis of Dent’s disease

The rare Dent’s disease manifests with medullary nephrocalcinosis, nephrolithiasis, hypercalciuria, low molecular weight proteinuria and other tubular dysfunctions, rickets or osteomalacia, and renal failure, in various combinations. It is a recessive X-linked condition. Clinicians consider family history a fundamental pointer to its diagnosis, but this is not invariably the case as clearly pointed out by the two reported cases.     

Dementia in Parkinson’s disease

Opinion statement One of the more recently recognized problems in treatment of patients with Parkinson’s disease (PD) is development of cognitive dysfunction and, in many cases, frank dementia. As patients with PD live longer, because of improved care and treatment of motor symptoms, dementia in PD is becoming a major contributor to morbidity in the illness. Prevalence studies suggest that up to 30% of patients with PD develop dementia. Dementia in PD patients is often a multifactorial condition. Neuropathologic changes caused by PD itself may cause memory loss. However, some patients with PD and memory decline also have pathologic changes that are more consistent with Alzheimer’s disease. Many PD patients have a mix of the two types of pathology. Other factors, such as underlying illnesses, medication side effects, and interaction of therapeutic agents, may contribute to cognitive changes in PD patients. Predictors of development of dementia in PD include advancing age and severity of neurologic symptoms, which may interact with one another to produce this effect. Recent work suggests that tobacco use also may increase risk of PD dementia, despite its possible protective effect against development of PD itself. Presence of psychiatric illness, especially depression, may interfere with cognition and exacerbate memory loss. Reduction in the dose of dopaminergic agents and of other medications may be helpful in partially improving cognitive function in some cases. The balance between improvement of motor function and preservation of cognitive abilities must be weighed, and it is important for clinicians to discuss this trade-off with patients and their families. At this time, there is no US Food and Drug Administration-approved pharmacologic treatment for dementia in PD. However, medication used to treat Alzheimer’s disease, such as acetylcholinesterase inhibitors, may slow progression of memory loss in some PD patients. Based on work from small double-blind studies, open-label trials, and case reports, cholinesterase inhibitors may be tried for treatment of dementia in PD, as long as the patient and caregivers understand that these agents are being used on an off-label basis. Surgical intervention, such as deep brain stimulation of the subthalamic nucleus or globus pallidus internus, although useful for treatment of motor symptoms in some PD patients, does not improve cognitive function in most cases and may actually worsen cognition in patients with pre-existing dementia. There is no specific exercise regimen or dietary guidelines for patients with PD who develop dementia. However, patients should be encouraged to lead a healthy lifestyle; this may improve overall well-being, which could impact positively on cognition function. Similarly, although assistive devices have not been developed for people with PD who have memory loss, any aid that increases mobility will probably improve mental and physical function. Clinicians should be mindful of the increased caregiver burden posed by PD patients who also have dementia. They should intervene appropriately to prevent caregiver distress and “burn out.” Herbal and nutritional supplements have not been shown in clinical trials to be beneficial for treatment of any type of dementia, and thus are not recommended for PD patients with cognitive decline.     

Psychosis in Parkinson’s disease

Opinion statement Psychotic symptoms are common and can be a major therapeutic challenge in patients with Parkinson’s disease (PD). PD-related psychosis is usually characterized by visual hallucinations or delusions and is most often induced by antiparkinsonian medications. However, other medical conditions, psychoactive medications, sleep disturbances, mood disorders, and cognitive impairments are relevant risk factors. Patients with PD should be continually monitored for factors that can trigger the development of psychotic symptoms, including minor symptoms. This includes ongoing critical re-evaluation of the therapeutic regimen, with adjustments as indicated to optimize function across motor, cognitive, and psychiatric domains. Treatment strategies to reduce psychotic symptoms are determined by the clinical picture. “Benign” symptoms may require only education and reassurance. Antipsychotic medications are required for disabling symptoms and emergency hospitalization may be required for agitation that affects the safety of the patient or others. Medication management is often complex and includes elimination or reduction of antiparkinsonian agents (although this can compromise motor function), management of medical comorbidities, and use of atypical antipsychotics. Clozapine and quetiapine are regarded as the most safe and effective atypical neuroleptics in PD patients. Cholinesterase inhibitors can enhance cognition and may reduce psychotic symptoms.     

Depression in Parkinson’s disease

Opinion statement  

Pain in Parkinson’s disease

Opinion statement Pain is reported by nearly 50% of patients with Parkinson’s disease. In some patients, it can be more debilitating than the motor deficits. In order to identify the appropriate treatment strategy for each patient, it is useful to categorize pain syndromes as follows: 1) low DOPA (end of dose wearing off, diphasic, or early morning) painful states are associated with inadequate levels of dopamine receptor stimulation; 2) high DOPA (peak dose) painful states occur at times of maximum levodopa efficacy; and 3) many patients report pain that has no obvious relation to dopaminergic medications or may even be caused by other conditions. Low DOPA painful states are best treated by trying to provide more continuous dopaminergic stimulation and thereby reduce or prevent the number and duration of “off” periods. Adding or increasing the dose of direct-acting dopamine receptor agonists or of catechol-o-methyl transferase inhibitors is the best first-line strategy. Other approaches include increasing the frequency of immediate-release levodopa preparations or using controlled-release preparations. More invasive approaches should be considered only when simpler methods fail. These include deep brain stimulation to the pallidum or the subthalamic nucleus, or direct duodenal continuous infusion of levodopa in patients who are unable to undergo surgery. Pain associated with excessive dopaminergic stimulation usually is a result of dystonia or severe chorea. Reduction of levodopa is the first step in attempting to diminish high DOPA states, followed by reduction or cessation of other dopaminergic agents such as selegiline, catechol-o-methyl transferase inhibitors, or direct-acting dopamine receptor agonists. Adding amantadine can reduce chorea significantly and it should be tried if the potential and actual side effects are tolerable to the patient. Deep brain stimulation is a good final option if medication adjustments are ineffective. Nonspecific pains of Parkinson’s disease can be difficult to treat. The effective use of central pain suppressant or analgesics is anecdotal and difficult to verify. In untreated early disease, generalized pain or pain related to joint or muscle immobility may be reduced by effective treatment of the underlying Parkinson’s disease.     

Necrotizing crescentic immunoglobulin A glomerulonephritis in adult-onset Still’s disease

Clinical and Experimental Nephrology -     

Role of mesenteric component in Crohn’s disease: A friend or foe?

Crohn’s disease (CD) is a complex and relapsing gastrointestinal disease with mesenteric alterations. The mesenteric neural, vascular, and endocrine systems actively take part in the gut dysbiosis-adaptive immunity-mesentery-body axis, and this axis has been proven to be bidirectional. The abnormalities of morphology and function of the mesenteric component are associated with intestinal inflammation and disease progress of CD via responses to afferent signals, neuropeptides, lymphatic drainage, adipokines, and functional cytokines. The hypertrophy of mesenteric adipose tissue plays important roles in the pathogenesis of CD by secreting large amounts of adipokines and representing a rich source of proinflammatory or profibrotic cytokines. The vascular alteration, including angiogenesis and lymphangiogenesis, is concomitant in the disease course of CD. Of note, the enlarged and obstructed lymphatic vessels, which have been described in CD patients, are likely related to the early onset submucosa edema and being a cause of CD. The function of mesenteric lymphatics is influenced by endocrine of mesenteric nerves and adipocytes. Meanwhile, the structure of the mesenteric lymphatic vessels in hypertrophic mesenteric adipose tissue is mispatterned and ruptured, which can lead to lymph leakage. Leaky lymph factors can in turn stimulate adipose tissue to proliferate and effectively elicit an immune response. The identification of the role of mesentery and the crosstalk between mesenteric tissues in intestinal inflammation may shed light on understanding the underlying mechanism of CD and help explore new therapeutic targets.     

Sleep disorders in Parkinson’s disease

Sleep disorders in Parkinson's disease (PD) are frequent and have numerous etiologies. Both nighttime sleep disturbances and daytime sleepiness can occur. The key to effective treatment is appropriate diagnosis. A careful interview of the patient and his or her bed partner provides direction for additional evaluations. Referral to a sleep specialist for quantitative studies is necessary to evaluate for rapid eye movement (REM) sleep behavior disorder, sleep apnea, periodic limb movements, and other sleep disorders. Excessive daytime sleepiness may be attributed to interrupted nighttime sleep or daytime medications (particularly the dopamine agonists) or it may be intrinsic to PD. When the diagnosis is established, treatment is directed toward the primary sleep disturbance. Fragmented sleep due to recurrence of PD symptoms may improve with the use of long-acting preparations of carbidopa/levodopa. Sleep apnea is treated using continuous positive airway pressure, and REM sleep behavior disorder may improve using pharmacologic interventions, although controlled trials are lacking. Restless legs syndrome and periodic limb movements during sleep are treated with direct dopaminergic agonists at bedtime. Excessive daytime sleepiness related to the use of direct dopaminergic agonists may improve with dosage reduction or discontinuation. Stimulants such as modafinil may provide modest benefit.     

Nutritional therapies in Parkinson’s disease

Advise patients with Parkinson's disease (PD) to consume a balanced diet, with special attention to adequate intake of dietary fiber, fluids, and macro- and micronutrients. Regularly reassess patients' nutritional history and anthropomorphic measures (height and weight), particularly in patients with advanced disease. PD-related psychosocial as well as physical and cognitive limitations increase susceptibility to subacute and chronic malnutrition. Nutritional requirements may change with PD progression or after surgical therapy for PD. Patients and caregivers may benefit from counseling by a dietician who is knowledgeable about the nutritional risks and needs of PD. Regularly inquire about dysphagia symptoms, and consider speech therapy consultation for clinical and modified barium-swallowing evaluations and management recommendations. Although non-oral delivery options of dopaminergic therapy are increasing, severe dysphagia may warrant percutaneous endoscopic gastrostomy tube placement for nutritional support and more reliable PD medication dosing. Analyze vitamin B(12) and D concentrations at regular intervals. Both vitamins are frequently deficient in elderly persons but may not be routinely checked by primary care physicians. Record over-the-counter and nutritional supplement medications at each visit, and assist patients in periodically re-evaluating their potential benefits, side effects, drug interactions, and costs. To date, clinical trials of antioxidant vitamins and nutritional supplements have provided insufficient evidence to support routine use for PD in the clinic. Data from several clinical trials of antioxidant vitamins/nutritional supplements are expected in the near future. Consider altering medication dosing in relation to meals to help with mild to moderate motor fluctuations. Patients with severe motor fluctuations may benefit from adapting the 5:1 carbohydrate-to-protein ratio in their daily meals and snacks. Following a "protein redistribution" diet is logistically more difficult and less palatable, and therefore less frequently recommended. To ensure adequate protein intake, a registered dietician should supervise patients who follow either of these diets.     

A new classification for Freiberg’s disease

IntroductionFreiberg’s osteochondrosis is an uncommon cause of foot pain. Following a national survey circulated by the British Foot and Ankle Society it was found that no classification is used to guide surgical treatment. This study aimed to create a simple, reproducible CT based classification to preoperatively plan whether an osteotomy is required.MethodsA retrospective review of 24 CT scans of new Freiberg's diseasediagnoses over a 10 year period was conducted. These images were assigned a study number and anonymised. The scans were then reviewed in their entirety by three independent specialists who determined whether an osteotomy would be of benefit. The sagittal CT slice that displayed the widest portion of proximal articular margin of the proximal phalanx was identified and divided the articular surface into 2 zones - plantar and dorsal and this formed the basis for our classification. These sagittal slices were then reviewed independently by two surgeons to determine if patients had disease in one or both zones and re-reviewed two weeks later to assess intra-observer reliability.ResultsAll 24 cases involved the second metatarsal. From reviewing the sagittal CT slices, it was felt that 18 patients were suitable for osteotomy and 6 were suitable for debridement +/− arthroplasty alone. The current classification demonstrated that 18 patients had disease confined to zone 1 only and the remaining patients had disease in both zones. Inter-observer reliability assessment had 95.8% agreement (Krippendorff’s Alpha 0.897). Intra-observer reliability was 100%. Correlation of those observed to have isolated zone 1 disease and suitability for osteotomy was absolute (Pearson r = 1).ConclusionDividing the metatarsal head into two zones on the widest sagittal slice of the CT scan offers an easy reproducible way to preoperatively plan surgical treatment for Freiberg’s osteochondrosis. Patients with isolated zone 1 disease should be suitable for an osteotomy.     

Vitamin D in chronic kidney disease: is the jury in?

Vitamin D shows promise for improving diverse health outcomes among patients with chronic kidney disease. Observational studies of vitamin D medications have contributed important evidence for broad beneficial clinical effects of vitamin D beyond actions on bone. However, such studies are limited by the potential for confounding by indication. A large randomized controlled trial is now needed to test the hypothesis that vitamin D therapy improves clinical outcomes in patients with kidney disease.     

Dent��s disease: clinical features and molecular basis

Dent’s disease is an X-linked recessive renal tubulopathy characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. LMWP is the most constant feature, while the other clinical manifestations show wide variability. Patients also present variable manifestations of proximal tubule dysfunctions, such as aminoaciduria, glucosuria, hyperphosphaturia, kaliuresis, and uricosuria, consistent with renal Fanconi syndrome. Dent’s disease affects mainly male children, and female carriers are generally asymptomatic. In two-thirds of patients, the disease is caused by mutations in the CLCN5 gene, which encodes the electrogenic chloride/proton exchanger ClC-5. A few patients have mutations in OCRL1, the gene associated with the oculocerebrorenal syndrome of Lowe, which encodes a phosphatidylinositol-4,5-biphosphate-5-phosphatase (OCRL1). Both ClC-5 and OCRL1 are involved in the endocytic pathway for reabsorption of LMW proteins in the proximal tubule. This review will provide an overview of the important phenotypic characteristics of Dent’s disease and summarize the molecular data that have significantly increased our comprehension of the mechanisms causing this disease.     

Laparoscopic ileocecal resection in Crohn’s disease

Background: Despite some encouraging preliminary results, the role of laparosropic surgery in the treatment of Crohns disease (CD) is a subject of controversy and still under evaluation. The aim of this case-matched study was to compare the postoperative course of laparoscopic and open ileocecal resection in patients with CD in order to define the potential role of laparoscopic surgery in CD. Methods: From 1998 to 2001, 24 consecutive patients with isolated Crohns terminal ileitis treated by laparoscopic ileocecal resection (laparoscopy group) were compared with 32 patients matched for age, gender, duration of disease, preoperative steroid treatment, fistulizing disease, and associated surgical procedure, and treated by open resection (open group). Results: In the laparoscopy group, four procedures (17%) were converted. There were no deaths. The morbidity rate was 20% in the laparoscopy group and 10% in the open group (NS). There was no significant difference between the two groups in operating time, size of bowel resection and resection margin, postoperative morphine requirement, resumption of intestinal function, tolerance of solid diet, or length of hospital stay. Conclusions: Laparoscopic ileocecal resection in CD is safe and effective, even for fistulizing disease. There are no significant differences between laparoscopic and open ileocecal resection, especially in terms of the mortality and mortality rates. Consequently, because laparoscopic surgery seems to offer cosmetic advantages, it should be considered the procedure of choice for patients with ileocecal CD.     

Phlegmonous-infection in first degree Dupuytren’s disease

Dupuytren’s disease belongs to the group of so called fibromatoses and is considered to be a non infectious disease. Since first degree Dupuytren’s disease is generally not operated upon, we want to report the unexpected finding of phlegmonous-abcessing infection in nodules in Dupuytren’s disease in a 61 year old patient, who was treated surgically because of complaining painful symptoms in first degree nodules in his palm without clinically visible signs of infection.     

Do we need to do overcorrection in Blount’s disease?

Purpose

In order to prevent recurrent deformity, overcorrection in Blount’s disease has been a common practice by most paediatric orthopaedic surgeons. However, some patients have persistent valgus alignment resulting in awkward deformity. The femoro-tibial angle (FTA) was measured in this series of cases to determine the necessity of such practice.

Method

During 1998–2010, patients with Blount’s disease stage 2 by Langenskiold, aged from 30 to 40 months who had failed from bracing and underwent valgus osteotomy were included. Seventeen legs had postoperative FTA 7–13° (group 1) and 48 legs had postoperative FTA more than 13° (group 2). ROC curve was used to determine the appropriate FTA that was suitable to prevent recurrence.

Results

Four legs had recurrence (28.6 %) in group 1 and six legs (12.5 %) had recurrence in group 2. Chi-square test between two groups were not statistically significant in recurrence (p = 0.434). Age and BMI were not statistically significant between recurrent and non-recurrent groups. The ROC curve shows that overcorrection more than 15° did not show benefit to prevent the recurrence in Blount’s stage 2.

Conclusion

Our study showed that the overcorrection group had non-statistically significant recurrence compared to the non-overcorrection group, and overcorrection more than valgus 15° has no benefit to prevent recurrence.     

Preiser’s disease

Preiser’s disease is a rare condition involving avascular necrosis of the scaphoid, in part or in whole. Diagnosis currently is made most frequently by standard radiographs and magnetic resonance imaging (MRI). Treatment options are varied because no large series of comprehensive results has been reported. Vascularized or conventional bone grafting, proximal row carpectomy, and scaphoid excision/4 bone fusion are performed most commonly. If possible, every attempt to save the scaphoid should be made.