De novo minimal change disease

Beyond the acute posttransplantation period, glomerular causes of proteinuria in the renal allograft include recurrent glomerulopathy, transplant-associated entities, and de novo disease. We present a case of de novo minimal change disease with reversible acute renal failure occurring 2.5 years posttransplantation in a 56-year-old man. The cause of end-stage renal disease in the native kidney was membranous glomerulopathy. De novo minimal change disease in the renal allograft is an extremely rare entity requiring stringent clinical-pathological criteria for diagnosis. Many of the cases previously reported as de novo minimal change disease fail to meet these criteria. We review the eight reported cases that appear to fulfill a strict definition of minimal change disease in the context of the current report.     

The role of germline polymorphisms in the T-cell receptor in susceptibility to ankylosing spondylitis

The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda > or = 1.6) at the TCRA/D locus was excluded (LOD score < -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis.      

Determinants of Achieving Early Blood Pressure Control with Monotherapy in a Primary Care Setting

This study sought to identify the determinants of early blood pressure (BP) control associated with monotherapy in hypertensive individuals being managed in the primary care setting. The Valsartan Intensified Primary Care Reduction of Blood Pressure (VIPER‐BP) study, was a multicenter, randomized controlled trial of an intensive approach to BP management. During a standardized run‐in, 2185 participants commenced monotherapy (valsartan 80 mg/d) for 14 to 28 days. A total of 1978 participants aged 59±12 years (60% men) completed the run‐in phase. Of these, 15.1%, 43.5%, and 41.4% participants had an initial BP target of ≤125/75, 130/80, and 140/90 mm Hg, respectively. A total of 416 of 2185 participants (19.0%) subsequently achieved their individual BP target during run‐in with a mean BP change of −22.6±12.1/−12.9±8.2 mm Hg vs −4.2±16.2/−3.0±9.6 mm Hg for the rest (P<.001). These early responders were more likely to be women (adjusted odds ratio, 1.41; 95% confidence interval, 1.10–1.80), had lower BP at baseline, were less likely to have been treated previously (or for less time), and had a less stringent BP target. An initial period of monotherapy achieved BP control in a high proportion of hypertensive individuals with key groups (including women and de novo cases) more likely to show an early BP response.

Elevated blood pressure (BP), or hypertension, represents one of the most preventable and yet seemingly intractable contributors to cardiovascular disease (CVD). Overall, hypertension is estimated to contribute to around 30% to 40% of all‐cause or CVD‐related case fatalities in high‐income countries such as the United States.¹ A critical factor in this phenomenon is the high proportion of identified individuals with hypertension who remain above their BP target and therefore at sustained elevated risk for a primary or secondary cardiovascular event.² Given the volume of cases, the majority of such individuals are managed in the primary care environment using office‐based measurements of BP, although there is increasing focus on 24‐hour ambulatory monitoring and home‐based monitoring³ to minimize potential white‐coat or masked hypertension and inappropriate or foregone treatment.⁴ In Australia, nearly 1 in 10 primary care encounters is related to hypertension⁵—more than any other single contributor to health care activity. As indicated, despite an array of effective pharmacologic agents, particularly when applied in combination (preferably a single pill to encourage treatment adherence), BP control rates remain suboptimal.Beyond the application of pharmacotherapy, there is strong evidence, including a Cochrane review of the literature, that more intensive and structured management in the primary care setting will significantly improve BP control rates.⁶ We therefore conducted the multicenter, randomized Valsartan Intensified Primary Care Reduction of Blood Pressure (VIPER‐BP) study⁷ to test the clinical effectiveness and overall safety of a more intensive and structured approach to optimizing BP control in a group of individuals with persistently high BP levels in primary care. During the randomized component of comparing the VIPER‐BP intervention (n=1038) with an enhanced form of usual care (n=524), the primary endpoint (individual risk‐based BP target) was achieved in 36.2% vs 27.4% of participants, respectively (adjusted relative risk 1.28 in favor of the intervention; P=.001) and the classical BP target of ≤140/90 mm Hg in 63.5% vs 54.0% of participants (adjusted relative risk 1.18 in favor of the intervention; P<.001).⁸ However, prior to randomization, a total of 2185 participants were exposed to a standardized run‐in period comprising clinical profiling and low‐dose angiotensin receptor blockers (ARBs) for 28 days.     

CHF5074, a novel γ-secretase modulator,attenuates brain β-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease

Background and purpose:

We evaluated the effects of 1-(3′,4′-dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a new γ-secretase modulator, on brain β-amyloid pathology and spatial memory in transgenic mice expressing the Swedish and London mutations of human amyloid precursor protein (hAPP).

Experimental approach:

Sixty 6-month-old hAPP mice were treated for 6 months with CHF5074 or ibuprofen (375 ppm in the diet) or standard diet. Twenty-one wild-type mice received standard diet.

Key results:

Compared with transgenic controls, CHF5074 treatment significantly reduced the area occupied by plaques in cortex (P = 0.003) and hippocampus (P = 0.004). The number of plaques were also reduced by CHF5074 in both cortex (P = 0.022) and hippocampus (P = 0.005). Plaque-associated microglia in CHF5074-treated animals was lower than in transgenic controls in cortex (P = 0.008) and hippocampus (P = 0.002). Ibuprofen treatment significantly reduced microglia area in cortex and hippocampus but not β-amyloid burden. On the last day of the Morris water maze, transgenic controls performed significantly worse than the non-transgenic animals and the CHF5074-treated transgenic mice, on the swimming path to reach the hidden platform. Ibuprofen-treated animals did not perform significantly better than transgenic controls.

Conclusions and implications:

Chronic CHF5074 treatment reduced brain β-amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel γ-secretase modulator is a promising therapeutic agent for Alzheimer''s disease.     

Genistein aglycone reverses glucocorticoid-induced osteoporosis and increases bone breaking strength in rats: a comparative study with alendronate

Background and purpose:

Glucocorticoid-induced osteoporosis (GIO) is the leading cause of secondary osteoporosis. Clinical evidence suggests a role for genistein aglycone in the treatment of post-menopausal osteopenia although proof of efficacy in comparison with currently available treatments is still lacking. To clarify this issue, we investigated the effects of genistein on bone compared with alendronate in experimental GIO.

Experimental approach:

A total of 28 female Sprague-Dawley rats were used. GIO was induced by daily injections of methylprednisolone (MP; 30 mg·kg⁻¹ s.c.) for 60 days. Sham GIO animals (Sham-MP) were injected daily with the MP vehicle. At the end of the osteoporosis development period, MP rats were randomized to receive: vehicle (n= 7), genistein aglycone (5 mg·kg⁻¹ s.c.; n= 7) or alendronate (0.03 mg·kg⁻¹ s.c.; n= 7). Treatment lasted 60 days. Sham-MP animals were treated with vehicle for an additional 60 days. At the beginning and at the end of treatments, animals were examined for bone mineral density and bone mineral content. Bone-alkaline phosphatase and carboxy-terminal collagen cross links were determined; femurs were removed and tested for breaking strength and histology.

Key results:

Genistein aglycone showed a greater increase in bone mineral density, bone mineral content and in breaking strength than alendronate and significantly increased bone-alkaline phosphatase (bone formation marker), reduced carboxy-terminal collagen cross links (bone resorption marker), compared with alendronate. Both treatments improved bone histology and the histological score.

Conclusion and implications:

The results strongly suggest that the genistein aglycone might be an alternative therapy for the management of secondary osteoporosis.     

Metrizamide computed tomography cisternography: pediatric applications

The methodology and clinical use of metrizamide (Amipaque) computed tomography (CT) cisternography are described as applied in the cases of 22 children with morphologic and physiologic abnormalities affecting the cranial portion portion of the central nervous system. In contrast to pneumoencephalography, CT cisternography affords equivalent or superior visualization of the basal cranal subarachnoid spaces with simpler technique and low morbidity. Intrathecal metrizamide enchancement in children causes a very low incidence of side effects.     

Comparative role of three-dimensional radiotherapy planning and inhomogeneity corrections in carcinoma of the tongue

The authors have assessed the role of computerized three-dimensional (3-D) and traditional (TD) radiotherapy planning and inhomogeneity corrections in improving target volume coverage and normal tissue sparing in carcinoma of the tongue. Coverage of target volumes in 3-D versus TD plans revealed the following. Volume receiving 95% of dose, clinical target volume (CTV): 1-68% versus 0-24%; gross tumour volume-lymph nodes (GTV-I): 0-80% versus 0-20%; gross tumour volume-primary tumour (GTV-II): 0-65% versus 0-26%. Dose to 95% of target volume CTV 77-92% versus 76-87%; GTV-I: 81-90% versus 61-88%; GTV-II: 82-93% versus 68-87%. Minimum dose to 5% of target volume, CTV: 77-93% versus 74-81%; GTV-I: 81-90% versus 61-88%; GTV-II: 76-93% versus 68-87%. Minimum dose to a volume of no less than 5% of the target volume, CTV: 93-98% versus 88-96%; GTV-I: 87-100% versus 88-97%; GTV-II: 86-98% versus 88-96%. A new parameter (inhomogeneity difference) was devised to study target volume dose homogeneity and was found to be very useful. Dose to two-thirds of the parotid glands in 3-D versus TD plans showed a mean of 46 versus 65% for right parotid glands and 44 versus 56% for left parotid glands in all patients. Better tumour dose homogeneity, increased mean tumour dose, avoidance of geographic misses and better parotid sparing was achieved in 3-D plans as compared to TD plans. We could not demonstrate any role for inhomogeneity corrections using currently available computerized dose algorithms.