Impact of histologic subtype and sarcomatoid transformation on metastasis in renal cell carcinoma: a single institute experience in 149 patients

Purpose

To compare the metastatic pattern and outcome of clear cell RCC (ccRCC) and papillary RCC (pRCC), and to assess the impact of sarcomatoid transformation on the disease spread and prognosis.

Materials and methods

This IRB-approved, HIPAA-compliant retrospective study included 149 consecutive patients (108 men; mean age 58 years; range 25–86) with metastatic RCC (ccRCC = 116, pRCC = 33), identified from imaging database. All available imaging studies and electronic records of these patients were reviewed to document pathological features, distribution and timing of metastasis, and survival. The metastatic pattern and survival was first compared between the ccRCC and pRCC groups, and then between those with and without sarcomatoid transformation; all 27 cases of sarcomatoid transformation occurred in the ccRCC group.

Results

Metastases were noted at presentation in 62 (42%) and after median 13 months in the remaining 87 (58%) patients. Lymph nodes (134/149), lung (125/149), and bone (60/149) were the most common metastatic sites, which did not differ between the RCC subtypes. Pancreatic (p = 0.0014) and renal (p = 0.046) metastases were more common in ccRCC, lymphangitic spread (p = 0.0003) and peritoneal metastasis (p = 0.039) more common in pRCC. In ccRCC, sarcomatoid transformation was associated with high-grade tumors (p < 0.0001), more frequently demonstrated lymphangitic (p = 0.016), pleural (p = 0.0018), and peritoneal metastases (p = 0.0002), and had shorter metastasis-free survival and overall survival (log-rank test, p < 0.0001). In the absence of sarcomatoid transformation, ccRCC had longer metastasis-free interval (median 22 months compared to 6 months) (p = 0.0238) and overall survival (median survival 48 months vs. 25 months) (p = 0.0193) compared to pRCC.

Conclusion

Histologic subtype, as well as the presence of sarcomatoid transformation, affects the metastatic pattern and metastasis-free survival of RCC. In the absence of sarcomatoid transformation, ccRCC has a better outcome than pRCC.

     

Chiral molecular self-assembly of phospholipid tubules: A circular dichroism study

We report on spectroscopic studies of the chiral structure in phospholipid tubules formed in mixtures of alcohol and water. Synthetic phospholipids containing diacetylenic moieties in the acyl chains self-assemble into hollow, cylindrical tubules in appropriate conditions. Circular dichroism provides a direct measure of chirality of the molecular structure. We find that the CD spectra of tubules formed in mixtures of alcohol and water depends strongly on the alcohol used and the lipid concentration. The relative spectral intensity of different circular dichroism bands correlates with the number of bilayers observed using microscopy. The results provide experimental evidence that tubule formation is based on chiral packing of the lipid molecules and that interbilayer interactions are important to the tubule structure.     

A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia

In sub-Saharan Africans, maternal mortality is unacceptably high, with >400 deaths per 100,000 births compared with <10 deaths per 100,000 births in Europeans. One-third of the deaths are caused by pre-eclampsia, a syndrome arising from defective placentation. Controlling placentation are maternal natural killer (NK) cells that use killer-cell immunoglobulin-like receptor (KIR) to recognize the fetal HLA-C molecules on invading trophoblast. We analyzed genetic polymorphisms of maternal KIR and fetal HLA-C in 484 normal and 254 pre-eclamptic pregnancies at Mulago Hospital, Kampala, Uganda. The combination of maternal KIR AA genotypes and fetal HLA-C alleles encoding the C2 epitope associates with pre-eclampsia [P = 0.0318, odds ratio (OR) = 1.49]. The KIR genes associated with protection are located in centromeric KIR B regions that are unique to sub-Saharan African populations and contain the KIR2DS5 and KIR2DL1 genes (P = 0.0095, OR = 0.59). By contrast, telomeric KIR B genes protect Europeans against pre-eclampsia. Thus, different KIR B regions protect sub-Saharan Africans and Europeans from pre-eclampsia, whereas in both populations, the KIR AA genotype is a risk factor for the syndrome. These results emphasize the importance of undertaking genetic studies of pregnancy disorders in African populations with the potential to provide biological insights not available from studies restricted to European populations.Although pre-eclampsia presents clinically with a diverse array of systemic symptoms, the underlying disease-causing mechanism starts with placentation when trophoblast cells invade the decidua. Here, they transform the uterine spiral arteries into large vessels that form the fetoplacental supply line (1, 2). In pre-eclampsia and other pregnancy disorders (fetal growth restriction, stillbirth, and recurrent miscarriage) known collectively as the great obstetric syndromes (GOSs), trophoblast fails to invade optimally (3). Pre-eclampsia and other GOSs occur in all populations, but women of African ancestry are significantly more at risk; thus, GOSs are responsible for much of the high maternal and fetal mortality rates seen in sub-Saharan Africa (SSA) (4). The genetic contribution to pre-eclampsia is supported by several studies and involves both maternal genes and paternal genes inherited by the fetus (5, 6).The wall of the uterus is the territorial boundary between two genetically different individuals: the mother and the fetus. The uterine mucosal immune system appears to define this maternal/placental boundary. The decidua must control placentation, because in its absence, the trophoblast infiltrates to a dangerous extent, causing the condition of placenta percreta (7). The decidua contains an abundant population of specialized natural killer (NK) cells. These uterine NK cells (uNK) express killer-cell immunoglobulin-like receptors (KIRs) that recognize trophoblast HLA-C ligands (8, 9). Both KIR and HLA-C are genetically variable, resulting in many possible combinations of maternal KIR and fetal HLA-C ligands (10). The KIR region is defined by two groups of haplotype: A and B. The KIR A haplotype has seven KIR genes, all encoding inhibitory receptors apart from KIR2DS4. In contrast, the KIR B haplotype contains a variable number of additional KIR, most of which encode activating receptors (11, 12). All HLA-C allotypes are KIR ligands and can be divided into two groups (carrying either C1 or C2 epitopes) that are distinguished by a dimorphism at position 80 and recognized by different KIR (13). Within a human population, the combination of KIR and HLA diversity distinguishes individuals and this extremely high variation is particularly evident in SSA populations. They exhibit less linkage disequilibrium (LD) between the KIR genes than other populations (14–16), and the KIR genes have greater allelic diversity (15, 16). A variety of diseases and clinical conditions has been associated with combinations of HLA-C and KIR genes. In previous case–control studies of pre-eclampsia in pregnant European women, we showed that, when the fetus carries a C2 epitope, maternal KIR AA genotypes are risk factors for pre-eclampsia, whereas the KIR2DS1 gene of maternal KIR B haplotypes is protective (8, 17). In the case–control study reported here, we test the hypothesis that these factors confer similar risk and protection to pregnant SSA women.     

Knowledge and attitudes towards HIV/AIDS among dental students of Jazan University,Kingdom Saudi Arabia

Objectives

To evaluate the knowledge and attitudes of dental students at Jazan University, Saudi Arabia; compare the differences in HIV/AIDS related knowledge and attitudes between the genders and years of study.

The illusion of client-centred practice

Abstract

Aim: A critical analysis of occupational therapy practice in the corporate health care culture in a free market economy was undertaken to demonstrate incongruence with the profession’s philosophical basis and espoused commitment to client-centred practice. Findings: The current practice of occupational therapy in the reimbursement-driven practice arena in the United States is incongruent with the profession’s espoused philosophy and values of client-centred practice. Occupational therapy differentiates itself from medicine’s expert model aimed at curing disease and remediating impairment, by its claim to client-centred practice focused on restoring health through occupational enablement. Practice focused on impairment and function is at odds with the profession’s core tenet, occupation, and minimizes the lasting impact of interventions on health and well-being. The profession cannot unleash the therapeutic power of human occupation in settings where body systems and body functions are not occupation-ready at the requisite levels for occupational participation. Conclusion: Client-centred practice is best embodied by occupation-focused interventions in the natural environment of everyday living. Providing services that are impairment-focused in unfamiliar settings is not a good fit for client-centred practice, which is the unique, authentic, and sustainable orientation for the profession.     

Sacral nerve stimulation for voiding dysfunction: One institution's 11-year experience

AIM: The purpose of this study was to review our institution's 11-year experience with SNS for the treatment of refractory voiding dysfunction. Dating back to 1993, it covers a span of time which describes the evolution of SNS as it includes PNE trials, non-tined (bone-anchored or fascial-anchored) leads, percutaneous tined leads with two-staged procedures, and even percutaneous pudendal trials. METHODS: A retrospective review was performed on SNS patients who received an implantable pulse generator (IPG) in our practice from 12/1993 to 12/2004. After Institutional Review Board approval, consents for chart review were obtained from 104 patients, representing 44% of this neuromodulatory patient population. RESULTS: Of our population, 87% were female and 13% were male. Average age at implant was 50 years +/- 13.4 years. Duration of symptoms before implantation was 116 months (range 9-600 months). Eighty percent were implanted for a predominant complaint of urinary urgency and frequency (U/F). Overall, 22% had U/F only, 38% had concomitant urge incontinence (UI), and 20% had concomitant mixed incontinence (MI). Twenty percent were treated for non-obstructive urinary retention (UR), with half of these associated with a neurogenic etiology. Additionally, 46.2% had pelvic pain, 58.6% had bowel complaints, and 51% reported sexual dysfunction. In patients with U/F, mean voiding parameters as described by pre-implant voiding diaries revealed the following: 12.4 (+/-5.1) voids per 24 hr; 2.3 (+/-1.8) voids per night; 5.0 (+/-4.7) leaks per 24 hr; and 2.3 (+/-2.6) pads per 24 hr. Statistically significant improvements post-implantation were noted with mean decreases in the following: 4.3 voids per 24 hr; 1.0 void per night; 4.4 leaks per 24 hr; and 2.3 pads per 24 hr (all P < 0.05). In the UR group a statistically significant improvement post-implantation was noted only in voids per night, with a mean decrease of 0.8 (P < 0.05). With a mean follow up of 22 months (range 3-162 months), sustained subjective improvement was >50%, >80%, and >90% in 69%, 50%, and 35% of patients, respectively. By quality of life survey, 60.5% of patients were satisfied and 16.1% were dissatisfied with current urinary symptoms. Only 13% (14 patients) abandoned therapy, making up a significant portion of those dissatisfied with current urinary symptoms. Good overall lead durability was seen (mean 22 months, range 1-121 months), with the first successful lead proving to be the most durable (mean 28 months, range 1.4-120 months). Lead durability decreased progressively with subsequent trials. Overall, 53% of patients experienced at least one reportable event (RE) attributable to either lead or IPG. A total of 126 REs were noted, with 97% mild-to-moderate in severity. REs included lack of efficacy, loss of efficacy, infection, hematoma/seroma, migration, pain, undesirable change in sensation, and device malfunction. In this population, 47.1% of leads were tined while 52.9% were non-tined. Tined leads had an overall lower RE rate as compared to non-tined leads: 28% and 73%, respectively. CONCLUSIONS: SNS is an effective method for treating certain types of voiding dysfunction. Although 53% of patients experienced at least one RE, 97% were mild-to-moderate and did not appear to affect the continued use of this therapy. With improved technology, such as percutaneous tined leads, the RE rate is decreasing. Further analyses of subsets of this population are currently underway.     

Mitochondrial α-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo

Alpha-synuclein is the major protein component of Lewy bodies, a cardinal pathological feature of the degenerating Parkinsonian brain. Alpha-synuclein has been reported to be able to intercalate into membranes via formation of an alpha-helical structure at its N-terminal end. Recent in vitro studies from various laboratories have demonstrated that α-synuclein can physically associate with mitochondria and interfere with mitochondrial function. α-Syn predominantly associates with the inner mitochondrial membrane, where it can apparently interact with complex I resulting in reduced mitochondrial complex I activity and increased free radical production. However, the effect of in vivo α-synuclein accumulation within dopaminergic neurons on mitochondrial function has not been thoroughly studied. Examination of transgenic animals which overexpress the familial mutant A53T form of the protein selectively within dopaminergic neurons reveals that A53T localizes to the mitochondrial membranes as monomers and oligomers particularly under conditions of proteasomal inhibitory stress, and that this localization coincides with a selective age-related mitochondrial complex I inhibition and decreased substrate-specific respiration along with increases in mitochondrial autophagy (mitophagy).     

Interaction study on garlic and atorvastatin with reference to nephrotoxicity in dyslipidaemic rats

A total of 56 male Sprague dawley rats of uniform weight and age were randomly divided into seven groups consisting of eight rats in each group. Groups 1, 2, and 3 served as plain control, dyslipidaemic control (DL), and atorvastatin control, respectively. Groups 4, 5, 6, and 7 received 1, 0.5, 0.25, and 0.75% fresh garlic w/w in feed, respectively in addition to the high-fat and high-cholesterol diet and administered with atorvastatin orally for 12 weeks at the rate of 10, 5, 7.5, and 2.5 mg/kg b.wt., respectively. Plasma creatinine was estimated at 4-week intervals, whereas histopathology, electron microscopy, and estimation of TBARS concentration in kidney were conducted at the end of experiment. The TBARS concentration in DL was significantly (P<0.05) increased when compared with groups 1, 3, 6, and 7. On histopathological examination, kidney sections of group 3 had mild degenerative changes in the tubules with fatty change in few tubules, while groups 4 and 5 exhibited mild-to-moderate degenerative and fatty changes in tubules with inter tubular hemorrhages. The electron microscopy of group 2 showed hypertrophy of Bowman's capsule, while that of group 4 showed secretary deposits in the cytoplasm. The interaction studies on kidney indicated that high dose of atorvastatin + garlic has negative safety profile when compared with groups having low dose of statin and high dose of garlic.