Considerations Regarding the Etiology and Future Treatment of Autosomal Recessive Versus Idiopathic Parkinson Disease

OPINION STATEMENT: We postulate that the frequently encountered grouping of different Parkinson disease (PD) variants into a single pathogenetic concept-rather than differentiation into its molecular subtypes-has hindered progress toward curative interventions. Parkinsonism is a clinical syndrome that in rare cases can be explained by a single genetic event or by a single environmental cause, thereby leading to monogenic PD and secondary parkinsonism, respectively. Under the former category, mutations in both alleles of the Parkin-encoding PARK2 gene leads to young-onset, autosomal recessive PD, in which neurodegeneration is restricted to dopamine-producing cells of the brainstem. Under the latter category, exposure to one of several environmental factors with neuroanatomic selectivity can cause rapid-onset, secondary parkinsonism most likely irrespective of the patient's age and genetic makeup. Sandwiched between these two extreme and rare types, the most common variant is referred to as late-onset, idiopathic PD. In extension of a disease model first proposed by Braak et al., we consider idiopathic PD the result of an encounter between one or several environmental triggers and one or more susceptibility alleles. Importantly, this interaction produces a pre-motor syndrome followed by the typical PD phenotype over a period of decades. In our opinion, this pathophysiological process should thus be viewed as a "complex disease." As is true for many complex human disorders, successful intervention for the common PD variant will likely occur when genetic leads as well as environmental contributors are targeted in parallel. However, successful proof-of-concept studies could arrive sooner, namely for select PD variants that can be attributed to a single genetic event and that are neuropathologically restricted. Therefore, the authors decided to focus the second portion of their review on treatment considerations regarding autosomal recessive PD cases that are caused by Parkin deficiency. We briefly draw attention to aspects of existing pharmacological and surgical therapies as they relate to the PARK2-linked variant; thereafter, we comment on new research avenues that are aimed at future therapeutic interventions to eventually slow or arrest the progression of a first variant of PD.     

BPH: Social Impact and Patient's Perspective

Benign prostatic hyperplasia (BPH) is a common condition in ageing men and although not a life-threatening disease, it can affect quality of life (QOL) to differing degrees. BPH progressively decreases patient self-esteem and lower urinary tract symptoms have also been shown to affect a patient's perceived sexuality. It has been shown that the impact of BPH on QOL is comparable to other disease conditions such as epilepsy requiring surgery and asthma, but worse, in certain aspects, than chronic obstructive pulmonary disease. With regard to the effect that BPH has on the patient's partner, the morbidity reported was due to sleep disturbance, disruption of social life, psychological burden, inadequate sex life, and fear of surgery or prostate cancer. Factors that influence a patient's desire to seek treatment have been identified and include bother, interference with daily activities, symptom frequency, worry, and embarrassment; patients also have a major concern about acute urinary retention (AUR) and BPH-related surgery. The reasons patients with BPH chose one therapy over another have been studied and it appears that patients prefer rapid symptom improvement, reduction in prostate size, no side-effects, and a decrease in the risk of AUR and surgery. The strongest influence was side-effects and the most important benefit was reduction in prostate size. Physicians clearly influence the final treatment decision, but they should be aware of patient preferences and consider them when they discuss treatment options with the patient.     

Comparing the Clinical and Economic Impact of Laparoscopic Versus Open Liver Resection

Background  

Laparoscopic liver resection has thus far not gained widespread acceptance among liver surgeons. Valid questions remain regarding the relative clinical superiority of the laparoscopic approach as well as whether laparoscopic hepatectomy carries any economic benefit compared with open liver surgery.     

Incidence of BK with Tacrolimus Versus Cyclosporine and Impact of Preemptive Immunosuppression Reduction

Our purposes were to determine the incidence of BK viruria, viremia or nephropathy with tacrolimus (FK506) versus cyclosporine (CyA) and whether intensive monitoring and discontinuation of mycophenolate (MMF) or azathioprine (AZA), upon detection of BK viremia, could prevent BK nephropathy. We randomized 200 adult renal transplant recipients to FK506 (n = 134) or CyA (n = 66). Urine and blood were collected weekly for 16 weeks and at months 5, 6, 9 and 12 and analyzed for BK by polymerase chain reaction (PCR). By 1 year, 70 patients (35%) developed viruria and 23 (11.5%) viremia; neither were affected independently by FK506, CyA, MMF or AZA. Viruria was highest with FK506-MMF (46%) and lowest with CyA-MMF (13%), p = 0.005. Viruria >/= 9.5 log(10) copies/mL was associated with a 3-fold increased risk of viremia and a 13-fold increased risk of sustained viremia. After reduction of immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction or graft loss. No BK nephropathy was observed. Choice of calcineurin inhibitor or adjuvant immunosuppression, independently, did not affect BK viruria or viremia. Viruria was highest with FK506-MMF and lowest with CyA-MMF. Monitoring and preemptive withdrawal of immunosuppression were associated with resolution of viremia and absence of BK nephropathy without acute rejection or graft loss.     

Impact of Postmastectomy Radiation Therapy in Prepectoral Versus Subpectoral Implant-Based Breast Reconstruction

Background

This study aimed to compare the impact of postmastectomy radiation therapy (PMRT) on outcomes after prepectoral versus subpectoral implant-based breast reconstruction with local deepithelialized dermal flap and acellular dermal matrix (ADM).

Methods

From 2010 to 2017, 274 patients (426 breasts) underwent prepectoral reconstruction. In this group, 241 patients (370 breasts) were not exposed to PMRT, whereas 45 patients (56 breasts) were exposed to PMRT. Of 100 patients (163 breasts) who underwent partial subpectoral reconstruction, 87 (140 breasts) were not exposed to PMRT, whereas 21 patients (23 breasts) were exposed. The outcomes were assessed by comparing complication rates between the pre- and subpectoral groups.

Results

A higher rate of capsular contracture was found for the prepectoral patients with PMRT than for those without PMRT (16.1 vs 3.5%; p?=?0.0008) and for the subpectoral patients with PMRT than for those without PMRT (52.2 vs 2.9%; p?=?0.0001). The contracture rate was three times higher for the subpectoral patients with PMRT than for the prepectoral patients with PMRT (52.2 vs 16.1%; p?=?0.0018). In addition, 10 (83.3%) of 12 cases with capsular contracture in the subpectoral cohort that received PMRT were Baker grades 3 or 4 compared with only 2 (22.2%) of 9 cases of the prepectoral group with PMRT (p?=?0.0092).

Conclusions

The patients undergoing subpectoral breast reconstruction who received PMRT had a capsular contracture rate three times greater with more severe contractures (Baker grade 3 or 4) than the patients receiving PMRT who underwent prepectoral breast reconstruction.