Body size and weight as predisposing factors in varicocele

OBJECTIVE: The literature regarding the constitutional type of children and adolescents with varicocele is inconsistent. The aim of this investigation was to examine a possible influence of weight, height and body mass index (BMI) on the formation of varicoceles during childhood and adolescence. MATERIAL AND METHODS: In a retrospective data analysis, 193 Caucasian children and adolescents aged 9-19 years (mean age 14.7 years) with left-sided varicocele grade 2-3 were studied. The weight, height and BMI of the subjects were compared with the age-correlated normal values currently accepted in Germany. Additionally, the familial disposition for varicocele and the occurrence of relevant concurrent diseases were considered. RESULTS: In the group of patients examined, the mean percentiles of weight (57th) and height (58th) were significantly above and the mean BMI percentile (42th) was significantly below the age-correlated 50th percentile for the normal population (p=0.019, 0.005 and 0.002). In our case material, 12.2% of all brothers of the patients had varicoceles. CONCLUSIONS: The results of this investigation suggest a correlation between physical appearance and the formation of a varicocele during childhood or adolescence. We were able to demonstrate that patients with varicocele were heavier and taller than an age-correlated normal population, but had a distinctly lower BMI. Further studies are needed to verify whether this rather athletic habitus, together with the postulated difference in muscle:fat ratio, represents an important etiologic factor for varicocele formation.     

Matrix metalloproteinase inhibitor Ro 28-2653 in combination with estramustine: tumor-reducing effects on hormone-sensitive prostate cancer in rats

Therapeutic efficacy of the novel matrix metalloproteinase (MMP) inhibitor, Ro 28-2653 (5-biphenyl-4-yl-5-[4-(-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione), has been shown in various models of different tumor entities. The tumor growth-reducing effect has been demonstrated in the orthotopic rat prostate Dunning model (subline MatLyLu). Based on these results we investigated Ro 28-2653 in combination with estramustine on the G subline of the Dunning tumor. This subline is characterized by a low metastatic ability and androgen sensitivity. Efficacy was determined by recording tumor growth in vivo by magnetic resonance imaging (MRI). Tumor cells were injected into the prostates of 81 Copenhagen rats. MRI was performed at day 100 and at day 126 after tumor cell injection. The duration of therapy was 17 days with daily oral application of Ro 28-2653 (100 mg/kg) and four i.p. injections of estramustine (7.5 mg/kg). Histological evaluations were conducted to provide further information about the effects on tumor morphology. Orthotopic tumor induction was successful in 100% of the animals. Tumor volume calculations with MRI showed a significant difference between the control groups, the animals treated with Ro 28-2653, and the animals treated with the combination of Ro 28-2653 and estramustine. The new MMP inhibitor Ro 28-2653 reduces tumor growth and provides a compatible therapeutic alternative for patients with prostate cancer.     

Cell-type-specific consequences of Reelin deficiency in the mouse neocortex, hippocampus, and amygdala

The disrupted cortical lamination phenotype in reeler mice and subsequent identification of the Reelin signaling pathway have strongly informed models of cortical development. We describe here a marker-based phenotyping approach to reexamine the cytoarchitectural consequences of Reelin deficiency, using high-throughput histology and newly identified panels of highly specific molecular markers. The resulting cell-type-level cytoarchitectural analysis revealed novel features of abnormal patterning in the male reeler mouse not obvious with less specific markers or histology. The reeler cortex has been described as a rough laminar inversion, but the data presented here are not compatible with this model. The reeler cortex is disrupted in a more complex fashion, with some regions showing a mirror-image laminar phenotype. Major rostrocaudal and cell-type-specific differences in the laminar phenotype between cortical areas are detailed. These and similar findings in hippocampus and amygdala have implications for mechanisms of normal brain development and abnormalities in neurodevelopmental disorders.     

Pertrochant?re Femurfrakturen

The objective of any surgical care of a trochanteric femoral fracture should be the achievement of a stable osteosynthesis that allows early full weight-bearing mobilisation of the patient, because long-term immobilisation soon becomes a vital threat to the affected patients who are usually elderly with correlating comorbidities. The anatomical references of the proximal femur and the structure of the hip joint contain some specifics that play an essential role in the incurrence of a trochanteric femoral fracture and the planning of the osteosynthesis as well. With reposition and fracture stabilisation particular importance must be attached to the collo-diaphyseal and the antetorsion angle so that they do not interfere with the functional interaction of the hip and knee joint. Uncomplex trochanteric fractures ordinarily stabilise sufficiently after reposition so that even an extramedullary implant can ensure full weight-bearing stability. With evermore distal fracture course and intertrochanteric comminution zone, rotational instability and pivot transfer of the fracture area to lateral and caudal are followed by an increase of the dislocating forces. These kinds of fractures (A2 and A3 according to the AO/ASIF classification) profit from an intramedullary and rotationally stable osteosynthesis. Basically primary total hip arthroplasty is a potential option for surgical care of a trochanteric fracture in elderly patients with relevant coxarthrosis. However this procedure can only be recommended in cases of a stable uncomplex fracture. The more the medial interlocking of the proximal femur is destroyed the more difficult it will be to primarily implant a total hip prosthesis with good offset and without a varus and rotational failure in the fracture zone.The current studies in the main show disadvantages due to increased complications in these patients, so that in cases of an unstable trochanteric fracture a primary osteosynthesis should be performed followed by total hip arthroplasty after fracture consolidation has occurred.     

Bone turnover markers as predictors of mortality risk in prostate cancer patients with bone metastases following treatment with zoledronic acid

Background

Clinical data have limited validity for predicting the survival of prostate cancer (PCa) patients with bone metastases. There is a need to improve the predictive evidence both for clinicians and patients.

Objective

To evaluate the predictive ability of serum bone markers for mortality risk in PCa patients with bone metastases.

Design, setting, and participants

We conducted a survival analysis in relation to bone markers in a subgroup of 52 patients treated with zoledronic acid (4 mg every 4 wk for 15 mo) in a prospective, multicentre trial during 2002–2005, about 4 yr after the end of the trial.

Measurements

Serum levels of total and bone-specific alkaline phosphatase, amino-terminal procollagen propeptides of type I collagen (PINP), cross-linked N-terminal (NTx) and cross-linked C-terminal telopeptides of type I collagen (ICTP), C-terminal telopeptides of type I collagen, prostate-specific antigen from the last visit of the treatment study, and clinical data were related to the overall survival (OS) status of patients in the follow-up. Univariate and multivariate Cox regression analyses with internal bootstrapping validation and concordance index calculations were performed.

Results and limitations

Out of the 52 patients followed, 34 died within a median follow-up of 13.8 mo, and 18 patients were alive at a median follow-up of 43.8 mo. The patients who died within the follow-up period had significantly higher concentrations of ICTP, NTx, and PINP than the surviving patients. Cox regression models with clinical data and bone markers showed that ICTP and PINP were most predictive for mortality risk in addition to the occurrence of skeletal-related complications and the continuation of treatment with zoledronic acid. Internal validation confirmed the reliability of the results, although the sample size was small.

Conclusions

PINP and ICTP can be considered suitable predictors for the OS of PCa patients with bone metastases.     

Primary care clinicians treat patients with medically unexplained symptoms

OBJECTIVE: There is no proven primary care treatment for patients with medically unexplained symptoms (MUS). We hypothesized that a long-term, multidimensional intervention by primary care providers would improve MUS patients' mental health. DESIGN: Clinical trial. SETTING: HMO in Lansing, MI. PARTICIPANTS: Patients from 18 to 65 years old with 2 consecutive years of high utilization were identified as having MUS by a reliable chart rating procedure; 206 subjects were randomized and 200 completed the study. INTERVENTION: From May 2000 to January 2003, 4 primary care clinicians deployed a 12-month intervention consisting of cognitive-behavioral, pharmacological, and other treatment modalities. A behaviorally defined patient-centered method was used by clinicians to facilitate this treatment and the provider-patient relationship. MAIN OUTCOME MEASURE: The primary endpoint was an improvement from baseline to 12 months of 4 or more points on the Mental Component Summary of the SF-36. RESULTS: Two hundred patients averaged 13.6 visits for the year preceding study. The average age was 47.7 years and 79.1% were females. Using intent to treat, 48 treatment and 34 control patients improved (odds ratio [OR]=1.92, 95% confidence interval [CI]: 1.08 to 3.40; P=.02). The relative benefit (relative "risk" for improving) was 1.47 (CI: 1.05 to 2.07), and the number needed to treat was 6.4 (95% CI: 0.89 to 11.89). The following baseline measures predicted improvement: severe mental dysfunction (P<.001), severe body pain (P=.039), nonsevere physical dysfunction (P=.003), and at least 16 years of education (P=.022); c-statistic=0.75. CONCLUSION: The first multidimensional intervention by primary care clinicians led to clinically significant improvement in MUS patients.     

Treatment of varicocele with reference to age: a retrospective comparison of three minimally invasive procedures

Background This study investigated whether the therapeutic efficacy and morbidity of three minimally invasive techniques for varicocele correction—laparoscopic varicocelectomy (LV), antegrade sclerotherapy (AS), and retrograde embolization (RE)—differed between children and adults. Methods During a 10-year period, 356 procedures for varicocele correction, including 122 cases of LV, 108 cases of AS, and 126 cases of RE, were performed for 314 patients at our institution. Of these patients, 223 were 19 years of age or younger (group 1), and 133 were older than 19 years (group 2). Diagnosis and postoperative results were established clinically and with the use of Doppler ultrasonography. The failure rates and complications for each procedure were retrospectively evaluated and compared between the two age groups. Results The median follow-up period was 69 months (range, 6–122 months). For 25 patients (19.8%), RE was not feasible for technical reasons. In both groups, LV had a lower failure rate than AS or RE, but the difference between LV and AS was not significant in group 1 (7.7(% vs 11.9%; p > 0.5). Also in group 1, AS was associated with fewer complications than LV 1 (4.5% vs 15.4%; p < 0.05). In group 2, LV was significantly more effective in correcting varicoceles than the other two techniques (p < 0.01). In this group, the complication rates for all three procedures did not differ significantly (p > 0.05). Conclusions In our experience, LV was more effective than AS or RE in correcting varicoceles. For children and adolescents, AS may be more indicated because of the slightly lower complication rate and similar recurrence rates, as compared with LV, for this age group. The higher incidence of postoperative hydrocele formation after LV warrants more refined techniques such as the lymphatic-sparing approach.     

Plasma osteopontin in comparison with bone markers as indicator of bone metastasis and survival outcome in patients with prostate cancer

BACKGROUND: The study was undertaken to evaluate the diagnostic and prognostic value of plasma osteopontin (OPN) in comparison to bone markers as well as the relationships between the markers and clinico-pathological factors in prostate cancer (PCa) patients. METHODS: OPN and the bone markers carboxyterminal-telopeptide of type I collagen, bone-specific alkaline phosphatase (bALP), and aminoterminal-propeptide of type I procollagen (PINP) were measured in 90 PCa patients with and without bone metastases, 35 patients with benign prostatic hyperplasia, and 29 healthy men. RESULTS: OPN and bone markers were significantly elevated in patients with bone metastases compared to the other groups. Significant correlations were found between all four-bone markers (r(s) = 0.43-0.79, all P < 0.01). OPN correlated with tumor grade (r(s) = 0.23, P < 0.05). In receiver-operating characteristics (ROC) analyses, OPN and bone markers were effective in distinguishing PCa patients with and without bone metastases showing areas under the curve (AUC) between 0.80 and 0.88 (all P < 0.001). OPN had an AUC of 0.85 that increased in combination with bALP up to 0.93 providing at the point with the highest diagnostic accuracy both a sensitivity and specificity of about 90%. Kaplan-Meier analyses and Cox proportional hazards regression models showed decreased survival of patients with high OPN and bone marker levels, while only high OPN and PINP were independent negative prognostic factors for PCa-related death. CONCLUSIONS: OPN alone or in combination with bone markers is useful as diagnostic marker in the detection of bone metastases and as prognosticator in the survival prediction in PCa patients.     

Para- and ortho-substitutions are key determinants of polybrominated diphenyl ether activity toward ryanodine receptors and neurotoxicity

Background

Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants that bioaccumulate in human tissues. Their neurotoxicity involves dysregulation of calcium ion (Ca²⁺) signaling; however, specific mechanisms have yet to be defined.

Objective

We aimed to define the structure–activity relationship (SAR) for PBDEs and their metabolites toward ryanodine receptors type 1 (RyR1) and type 2 (RyR2) and to determine whether it predicts neurotoxicity.

Methods

We analyzed [³H]ryanodine binding, microsomal Ca²⁺ fluxes, cellular measurements of Ca²⁺ homeostasis, and neurotoxicity to define mechanisms and specificity of PBDE-mediated Ca²⁺ dysregulation.

Results

PBDEs possessing two ortho-bromine substituents and lacking at least one para-bromine substituent (e.g., BDE-49) activate RyR1 and RyR2 with greater efficacy than corresponding congeners with two para-bromine substitutions (e.g., BDE-47). Addition of a methoxy group in the free para position reduces the activity of parent PBDEs. The hydroxylated BDEs 6-OH-BDE-47 and 4′-OH-BDE-49 are biphasic RyR modulators. Pretreatment of HEK293 cells (derived from human embryonic kidney cells) expressing either RyR1 or RyR2 with BDE-49 (250 nM) sensitized Ca²⁺ flux triggered by RyR agonists, whereas BDE-47 (250 nM) had negligible activity. The divergent activity of BDE-49, BDE-47, and 6-OH-BDE-47 toward RyRs predicted neurotoxicity in cultures of cortical neurons.

Conclusions

We found that PBDEs are potent modulators of RyR1 and RyR2. A stringent SAR at the ortho and para position determined whether a congener enhanced, inhibited, or exerted nonmonotonic actions toward RyRs. These results identify a convergent molecular target of PBDEs previously identified for noncoplanar polychlorinated biphenyls (PCBs) that predicts their cellular neurotoxicity and therefore could be a useful tool in risk assessment of PBDEs and related compounds.