A novel SNCA E83Q mutation in a case of dementia with Lewy bodies and atypical frontotemporal lobar degeneration

In this case report, we discuss a patient presenting with parkinsonism followed by a non-amnestic dementia with aphasic clinical features, as well as frontal dysexecutive syndrome. There was a family history of dementia with an autopsy diagnosis of “Pick's disease” in the proband's father. Neuroimaging of the patient revealed focal and severe temporal lobe and lesser frontoparietal lobe atrophy. At autopsy, there was severe frontotemporal lobar degeneration. Histologic evaluation revealed an absence of tau or transactivation response DNA-binding protein of 43 kDa (TDP) pathology but rather severe Lewy body deposition in the affected cortices. Genetic phenotyping revealed a novel missense mutation (p.E83Q) in exon 4 of the gene encoding α-synuclein (SNCA). This case study presents a patient with a novel SNCA E83Q mutation associated with widespread Lewy body pathology with prominent severe atrophy of the frontotemporal lobes and corresponding cognitive impairment.     

The Role of Smoking in Breast Cancer Development: An Analysis of a Mayo Clinic Cohort

Abstract:  The purpose of this study was to assess the predictive value of smoking history on breast cancer diagnosis in a referral clinic population. We conducted a case–control study using clinical data collected on 8,097 female patients (1,225 breast cancer cases and 6,872 controls) seen in the Mayo Clinic Breast Clinic between August 1, 1993 and November 31, 2003. Breast cancer patients and noncancer patients significantly differed with respect to age at time of the index visit (p < 0.001), number of pregnancies (p = 0.006), number of live births (p = 0.002), vital status at last known follow-up (p < 0.001), current menstruation (p < 0.001), age at menopause (p < 0.001), history of hysterectomy (p < 0.001), use of oral contraception (p = 0.05), duration of oral contraception use (p = 0.001), use of other exogenous hormones (p < 0.001), duration of exogenous hormone use (p = 0.05), breast pain at time of index visit (p = 0.002), smoking status (p < 0.001), and use of five or more alcoholic beverages per week (p = 0.002). After adjustment for these baseline characteristics, having a personal history of smoking was found to be predictive of breast cancer diagnosis (odds ratios [OR] = 1.25, p = 0.004). Other positive predictors for breast cancer diagnosis were: age (OR = 1.02, p < 0.001), history of hysterectomy (OR = 0.66, p < 0.001), prior use of oral contraception for more than 11 years (OR = 2.10, p < 0.001), and prior use of other exogenous hormones/estrogen (OR = 1.81, p < 0.001). In this referral practice having a personal history of smoking is predictive of breast cancer diagnosis. Further studies are needed to further explore this relationship.     

Tubular Cell and HIV-1 gp120 Interaction Products Promote Migration of Monocytes

Renal interstitial accumulation of monocytes is an important feature of HIV-associated nephropathy. We studied the effects of proximal tubular cell products (TCP) and proximal tubular cell-gp120 interaction products (TC-120IP) on the migration of monocytes across a modified Boyden chamber. TC-120IP promoted (P<0.001) the migration of monocytes when compared with TCP (TCP, 45.0 ± 5.9 vs. TC-120IP, 192.3 ± 39.5 migrated monocytes/field). This effect of TC-120IP on monocyte migration was dose dependent. Anti-MCP-1 (TCP, 24.7 ± 2.6; TC-120IP, 82.3 ± 5.5; TC120-IP + anti-MCP-1 antibody, 46.5 ± 3.5 migrated monocytes/field) as well as anti-TGF- antibodies (TCP, 25.8 ± 3.4; TC120-IP, 80.3 ± 6.9; TC-120IP + anti-TGF- antibody, 43.8 ± 5.6 migrated monocytes/field) partly attenuated TC-120IP-induced migration of monocytes across a filter. Moreover, anti-MCP-1 and anti-TGF antibodies showed an additive inhibitory effect on TC-1201P-induced migration of monocytes across a filter. These results suggest that TC-120IP-induced migration of monocytes may be mediated through the generation of MCP-1 and TGF- by tubular cells. The present study provides the basis for a hypothesis that HIV-1 gp120 protein may be contributing to the infiltration of monocytes in the renal interstitium of patients with HIV-associated nephropathy.     

Fas-mediated apoptosis of neutrophils in sera of patients with infection

In the presence of infection, neutropenia is considered to be a marker of poor prognosis; conversely, neutrophilia may not be a determinant of a better prognosis. Since apoptotic neutrophils are compromised functionally, we evaluated the effect of infection on neutrophil apoptosis. The rate of apoptosis was greater for neutrophils isolated from patients with infection than for healthy controls. Escherichia coli did not directly modulate the rate of neutrophil apoptosis. However, sera from infected patients promoted (P < 0.001) neutrophil apoptosis. Interestingly, the sera of patients with different types of infection (gram negative, gram positive, or culture negative) exerted a more or less identical response on neutrophil apoptosis. Sera of infected patients showed a fivefold greater content of FasL compared to controls. Moreover, anti-FasL antibody partly attenuated the infected-serum-induced neutrophil apoptosis. In in vitro studies, E. coli enhanced monocyte FasL expression. Moreover, conditioned media prepared from activated macrophages from control mice showed enhanced apoptosis of human as well as mouse neutrophils. On the contrary, conditioned media prepared from activated macrophages isolated from FasL-deficient mice induced only a mild degree of neutrophil apoptosis. These results suggest that neutrophils in patients with infection undergo apoptosis at an accelerated rate. Infection not only promoted monocyte expression of FasL but also increased FasL content of the serum. Because the functional status of apoptotic cells is compromised, a significant number of neutrophils may not be participating in the body's defense. Since neutrophils play the most important role in innate immunity, their compromised status in the presence of infection may transfer the host defense burden from an innate response to acquired immunity. The present study provides some insight into the lack of correlation between neutrophilia and the outcome of infection.     

Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X- linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide- exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.      

The effects of graft size and insertion site location during anterior cruciate ligament reconstruction on intercondylar notch impingement

Background

Intercondylar notch impingement is detrimental to the anterior cruciate ligament (ACL). Notchplasty is a preventative remodeling procedure performed on the intercondylar notch during ACL reconstruction (ACLR). This study investigates how ACL graft geometry and both tibial and femoral insertion site location may affect ACL-intercondylar notch interactions post ACLR. A range of ACL graft sizes are reported during ACLR, from six millimeters to 11 mm in diameter. Variability of three millimeters in ACL insertion site location is reported during ACLR. This study aims to determine the post-operative effects of minor variations in graft size and insertion location on intercondylar notch impingement.

Bottom-up analysis of emergent properties of N-acetylcysteine as an adjuvant therapy for COVID-19

N-acetylcysteine (NAC) is an abundantly available antioxidant with a wide range of antidotal properties currently best studied for its use in treating acetaminophen overdose. It has a robustly established safety profile with easily tolerated side effects and presents the Food and Drug Administration's approval for use in treating acetaminophen overdose patients. It has been proven efficacious in off-label uses, such as in respiratory diseases, heart disease, cancer, human immunodeficiency virus infection, and seasonal influenza. Clinical trials have recently shown that NAC's capacity to replenish glutathione stores may significantly improve coronavirus disease 2019 (COVID-19) outcomes, especially in high risk individuals. Interestingly, individuals with glucose 6-phosphate dehydrogenase deficiency have been shown to experience even greater benefit. The same study has concluded that NAC's ability to mitigate the impact of the cytokine storm and prevent elevation of liver enzymes, C-reactive protein, and ferritin is associated with higher success rates weaning from the ventilator and return to normal function in COVID-19 patients. Considering the background knowledge of biochemistry, current uses of NAC in clinical practice, and newly acquired evidence on its potential efficacy against COVID-19, it is worthwhile to investigate further whether this agent can be used as a treatment or adjuvant for COVID-19.     

Hydrocelectomy under local anaesthesia in a Nigerian adult population

Background

Hydrocele is abnormal collection of serous fluid in the tunica vaginalis or a patent processus vaginalis. It is commonly encountered in our practice and often requires surgical treatment. However in our setting and in many underdeveloped countries, availability of general anaesthetic service is poor due to lack of trained personnel and equipment.

Objectives

To ascertain the practicability and acceptability of hydrocelectomy under sedation and local anaesthesia in Nigerian adults with hydrocele

Patients and Methods

A prospective study was carried out over a two year period on patients that had hydrocelectomy at the surgery unit of the Obafemi Awolowo University Teaching Hospitals Complex, Wesley Guild Hospital, Ilesa. Consecutive patients with diagnosis of hydrocele who consented had hydrocelectomy using intramuscular diazepam sedation and spermatic-cord block with 0.5% plane xylocaine and the scrotum infiltrated with same along the line of incision.

Results

Fifty adult patients were studied: age range 15–94 years. Eighty percent of the patients had unilateral hydrocele and the commonest type was vaginal hydrocele (94%). All patients had hydrocelectomy, 96% were under local anaesthesia while 4% were converted to general anaesthesia. All patients except one prefer to have future surgery under such local anaesthesia and sedation.

Conclusion

Hydrocelectomy under local anaesthesia and sedation is practicable and was tolerated and accepted by the adults patients studied.