Renal medullary carcinoma

Renal medullary carcinoma is an epithelial malignant tumor arising from collecting duct epithelium. The tumor is almost exclusive to young black patients with the sickle cell hemoglobinopathies, mainly sickle cell trait (SCT). Most patients present with metastatic disease and have a worse prognosis. An African-American male with sickle cell disease (HbSCD) who was diagnosed to have renal medullary carcinoma is presented here. The clinical, histologic and radiologic features of this tumor are described. In the setting of advanced disease, treatment modalities have proved largely unsuccessful. Given the shared demographic, clinical and radiographic features of these patients, awareness and early diagnosis may prove essential in improving survival.     

A mutation in the cathepsin D gene (CTSD) in American Bulldogs with neuronal ceroid lipofuscinosis

We obtained DNA, brains, and eyes from American Bulldogs with neurodegeneration due to neuronal ceroid lipofuscinosis (NCL). The diagnosis of NCL was confirmed by detection of autofluorescent cytoplasmic inclusions within neurons throughout the brains, in retinal ganglion cells, and along outer limiting membranes of the retinas. Electron microscopy revealed that the inclusions had coarsely granular matrices surrounding well-delineated spherical structures and that the inclusions near the retinal outer limiting membranes were within photoreceptor cells, mostly cones. Affected American Bulldogs were homozygous for the A allele of a G to A transition in the cathepsin D gene (CTSD), which predicts the conversion of methionine-199 to an isoleucine. Only the G allele was detected in DNA samples from 131 randomly selected dogs representing 108 breeds other than American Bulldog; however, the A allele had a frequency of 0.28 among 123 genotyped American Bulldogs. Transmission analysis in a 99 dog pedigree of American Bulldogs indicated a probability of less than 10(-7) that alleles from any mutation unlinked to CTSD would be concordant with the pedigree and phenotypes of the dogs. Brain samples from affected dogs had 36% of the cathepsin D-specific enzymatic activity found in control dog brains; whereas, specific enzymatic activities of 15 other lysosomal enzymes were unchanged or increased. Compared to previously described NCLs in mice and sheep that completely lack cathepsin D activity, the clinical course of NCL in the American Bulldogs was less severe and more closely resembled that of many human NCLs.     

Therapeutic targeting of B7-H1 in breast cancer

INTRODUCTION: Breast cancer is the most common form of malignancy occurring in women worldwide. B7-H1 is a co-inhibitory molecule expressed by several types of tumors, including breast cancer. The aberrant expression of B7-H1 in breast cancer cells has been determined, its role in recruiting regulatory T cells into the tumor microenvironment has been elucidated and a strong link to B7-H1 induction in highly proliferative breast cancer has been provided. It has also been demonstrated that doxorubicin, a drug commonly used for breast cancer treatment, downregulates the cell surface expression of B7-H1 and upregulates its nuclear expression, which therefore suggests an anti-apoptotic role of B7-H1 in breast cancer. AREAS COVERED: This review illustrates the various factors involved in the induction of B7-H1 and its role in immune evasion and chemoresistance. It also provides potential therapeutic strategies for targeting B7-H1 in breast cancer. EXPERT OPINION: B7-H1 should be considered as a potential therapeutic target for breast cancer. Indeed, there is increasing evidence for the potential efficacy of B7-H1 blockade in the prevention of immune evasion by cancer cells. Additionally, B7-H1 targeting can be used in conjunction with other therapeutic modalities for improved efficacy and reduced toxicity. We expect that B7-H1 blockade in combination with other therapeutics will be a prime therapeutic strategy in the future.     

IMP-producing carbapenem-resistant Klebsiella pneumoniae in the United States

The emergence and spread of carbapenem-resistant Enterobacteriaceae (CRE) producing acquired carbapenemases have created a global public health crisis. In the United States, CRE producing the Klebsiella pneumoniae carbapenemase (KPC) are increasingly common and are endemic in some regions. Metallo-β-lactamase (MBL)-producing CRE have recently been reported in the United States among patients who received medical care in countries where such organisms are common. Here, we describe three carbapenem-resistant K. pneumoniae isolates recovered from pediatric patients at a single U.S. health care facility, none of whom had a history of international travel. The isolates were resistant to carbapenems but susceptible to aztreonam, trimethoprim-sulfamethoxazole, and fluoroquinolones. The three isolates were closely related to each other by pulsed-field gel electrophoresis and contained a common plasmid. PCR and sequence analysis confirmed that these isolates produce IMP-4, an MBL carbapenemase not previously published as present among Enterobacteriaceae in the United States.     

Neuroprotective and anti-stress effect of A68930 in acute and chronic unpredictable stress model in rats

The neurorescuing effect of A68930 (a potent selective D₁ agonist) and its role on the regulation of hypothalamus-pituitary-adrenal (HPA)-axis have been investigated. Acute (AS) and chronic unpredictable (CUS) stress models were used to evaluate the effect of A68930 on HPA-axis regulation in relation to the change in the fiber density and number of immunoreactive (ir) neurons of tyrosine hydroxylase (TH) and glucocorticoid receptor (GR) in the dopamine (DA) and GR rich brain regions in rats. CUS caused a significant decrease in the number of TH ir neurons in the striatum, medial forebrain bundle, ventral tegmental area and substansia nigra and GR in the cortex, striatum and hippocampus as compared to the non-stress controls (NS). Administration of A68930 (0.25 mg/kg i.p.) significantly normalized these CUS-induced alterations. We also examined the role of A68930 on stress-induced brain oxidative status. AS enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the cortex and striatum, while CUS reduced the activities of SOD and catalase (CAT) in the cortex, striatum and hippocampus, when compared with NS. Increased GSH-Px activity, with reduced glutathione and increased lipid peroxidation was observed in both AS and CUS in selected brain regions as compared to NS. Administration of A68930 normalized the antioxidant enzyme activities, replenished GSH and decreased the extent of lipid peroxidation. In conclusion, present findings suggest that the stress-induced immunoreactivity of TH and GR in distinct brain regions are modulated by A68930 leading to the normalization of HPA-axis response. Ours results show the therapeutic importance of DA D₁ agonist in stress-induced dopaminergic-related neurological disorders. A68930 also influenced the brain antioxidant machinery probably through the restoration of stress-induced changes in the dopaminergic system and its crosstalk with GR.     

Arterial compliance in adolescents and young adults receiving chronic hemodialysis

Increased vascular stiffness is an established risk marker of cardiovascular diseases (CVD) in adults with end-stage renal disease, but its role in pediatric patients remains to be defined. We prospectively examined arterial compliances of adolescents and young adults on hemodialysis (HD) using diastolic pulse wave analysis (DPWA). Each of the ten HD patients (age 17.3 +/- 3.9 years; mean +/- SD) had two DPWA tests within a three-week time period. DPWA measurement was performed before and hourly until the end of three-hour HD. Pre-HD large artery elasticity index (LAEI) was reduced in one patient and small artery elasticity index (SAEI) was reduced in another. Neither patient was hypertensive. Eight other patients had a reduction in both LAEI and SAEI. Among them, six patients had systolic and/or diastolic hypertension, and the other two were normotensive. Serum phosphorus correlated positively with stroke volume and cardiac output indices and negatively with SAEI. The reduction in BP during HD correlated with the amount of fluid removal. LAEI and SAEI were unchanged during HD. In conclusion, the reduction in LAEI and/or SAEI was observed in four normotensive patients, suggesting hypertension was not the only contributing factor for the reduced arterial compliances in our patients. The association between SAEI and serum phosphorus suggests that SAEI derived from DPWA can potentially be an early non-invasive, operator-independent, and volume-independent marker of CVD in adolescents and young adults receiving HD. Longitudinal studies with a larger sample size are needed to confirm our observation and speculation.     

Military-civic action: lessons learned from a brigade-level aid project in the 2003 war with Iraq

The primary mission of the military physician assigned to a combat-arms unit is to sustain the unit's fighting strength through prevention, primary medical care, and trauma resuscitation. Technical and organizational details of civic action assistance are not emphasized routinely during training. Real-world deployment, however, presents challenges approachable only with flexibility and improvisation. Historically, combatant commanders have recognized the health of civilians in their operational area as a target through which local acceptance of United States (US) intervention may be achieved. The medium-unit (battalion and brigade) physician may be charged with providing care to the host-nation populace. Because the mission's emphasis is one of public relations and not sustainable development, lasting medical benefits are not attained. This article addresses the challenge of on-the-spot military civic assistance. The experience of the 173d Airborne Brigade (Bde) Medical Section is used to color concepts with real events. The unit attempted to reach beyond the immediate directive in order to create a program of lasting results.