Accelerated pre‐senile systemic amyloidosis in PACAP knockout mice – a protective role of PACAP in age‐related degenerative processes

Dysregulation of neuropeptides may play an important role in aging‐induced impairments. Among them, pituitary adenylate cyclase‐activating polypeptide (PACAP) is a potent cytoprotective peptide that provides an endogenous control against a variety of tissue‐damaging stimuli. We hypothesized that the progressive decline of PACAP throughout life and the well‐known general cytoprotective effects of PACAP lead to age‐related pathophysiological changes in PACAP deficiency, supported by the increased vulnerability to various stressors of animals partially or totally lacking PACAP. Using young and aging CD1 PACAP knockout (KO) and wild type (WT) mice, we demonstrated pre‐senile amyloidosis in young PACAP KO animals and showed that senile amyloidosis appeared accelerated, more generalized, more severe, and affected more individuals. Histopathology showed age‐related systemic amyloidosis with mainly kidney, spleen, liver, skin, thyroid, intestinal, tracheal, and esophageal involvement. Mass spectrometry‐based proteomic analysis, reconfirmed with immunohistochemistry, revealed that apolipoprotein‐AIV was the main amyloid protein in the deposits together with several accompanying proteins. Although the local amyloidogenic protein expression was disturbed in KO animals, no difference was found in laboratory lipid parameters, suggesting a complex pathway leading to increased age‐related degeneration with amyloid deposits in the absence of PACAP. In spite of no marked inflammatory histological changes or blood test parameters, we detected a disturbed cytokine profile that possibly creates a pro‐inflammatory milieu favoring amyloid deposition. In summary, here we describe accelerated systemic senile amyloidosis in PACAP gene‐deficient mice, which might indicate an early aging phenomenon in this mouse strain. Thus, PACAP KO mice could serve as a model of accelerated aging with human relevance. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Immunohistochemical expression of prostate tumor overexpressed 1 in cystoprostatectomies with incidental and insignificant prostate cancer. Further evidence for field effect in prostatic carcinogenesis

Prostate tumor overexpressed 1 was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer. It has been suggested that overexpression of prostate tumor overexpressed 1 can contribute to the proliferative status of prostate tumor cells and, thus, to their biologic behavior. Prostate tumor overexpressed 1 and Ki-67 were immunohistochemically evaluated in prostate cancer, high-grade prostatic intraepithelial neoplasia, and normal-looking epithelium in 20 cystoprostatectomies and 20 radical prostatectomies with pT2a Gleason score 6 prostate cancer. The aim was to see whether there were differences in marker expression between cystoprostatectomies and radical prostatectomies. The proportions of prostate tumor overexpressed 1– and Ki-67–positive cells in the cystoprostatectomies and radical prostatectomies increased from normal-looking epithelium through high-grade prostatic intraepithelial neoplasia, away from and adjacent to prostate cancer, to prostate cancer. Prostate tumor overexpressed 1 expression in prostate cancer in cystoprostatectomies was lower than in radical prostatectomies, the differences being significant; there were significant differences in Ki-67 indices. In conclusion, our findings related to prostate tumor overexpressed 1 expression in high-grade prostatic intraepithelial neoplasia, evaluated adjacent and away from prostate cancer, and in incidental and clinical cancers give further support to the concept of field effect in prostatic carcinogenesis as well as to differences in the process of prostatic carcinogenesis between cystoprostatectomies and radical prostatectomies.     

Effects of stress and neuropeptides on airway responses in ovalbumin-sensitized rats

OBJECTIVE: The aim of this study was to investigate the influence of stress and neuropeptides on airway responses in ovalbumin (OVA)-sensitized rats. METHODS: Three experimental conditions were employed: neonatal capsaicin treatment, foot shock stress and OVA sensitization. For neuropeptide depletion, male Wistar rats were neonatally treated with capsaicin (50 mg/kg) or with control solution 2 days after birth. Ninety days later, they were injected with OVA and aluminum hydroxide (ED0) or no injection. Thereafter, rats of the stressed groups were individually placed in a shuttle box where they received 50 mild escapable foot shocks/day; the stressful stimuli were repeated until ED14, when the animals received OVA aerosol. Pulmonary mechanic function was measured before and after OVA challenge in anesthetized and mechanically ventilated rats. RESULTS: Data on ultrasonic vocalizations and corticosterone showed high levels of anxiety in stressed animals. As expected, a significant increment in airway elastance and resistance after the OVA challenge was found in sensitized rats compared to non-sensitized ones. Capsaicin treatment decreased the values of elastance in sensitized and non-stressed rats; however, after the OVA challenge, elastance was increased in stressed animals. No differences were found in the levels of resistance among sensitized and non-stressed rats; however, a reduced increment in resistance was verified in capsaicin-treated, stressed animals. CONCLUSIONS: Our results suggest that neurokinin depletion and stress may affect smooth muscle tonus around the airways during an anaphylactic reaction. These data suggest that stress and neuropeptides play a significant role in pulmonary function in OVA-sensitized rats.     

Outbreak of beriberi in an Indian population of the upper Amazon region, Roraima State, Brazil, 2008

Edema, parasthesias, and paresis affected 10 residents of an Indian community in Roraima state; three died. Mining with mercury occurs locally; caxirí, a traditional alcoholic drink, is consumed daily. We conducted a 1:2 unmatched case-control study; a case was an Indian from Uiramutã county (population of 9,127) who presented ≥ 1 of lower extremity edema, paresthesias, paresis, or weakness. Controls were asymptomatic Indians randomly selected from the population. We identified 90 cases (prevalence of 1%) and 180 controls; all were enrolled. Among cases, 79% were male, and the median age was 31 years. Ethnicity was Macuxí, and 49% had income. Cases had lower extremity edema (85%), upper extremity paresthesias (84%), and lower extremity weakness and pain (78%). Risk factors were male sex (odds ratio [OR] = 6.8; P < 0.001), age 31–40 years (OR = 5.63; P < 0.001), and consumption of caxirí (OR = 2.7; P < 0.003). Mercury exposure was not a risk. Thiamine therapy produced complete rapid clinical recovery in all cases, confirming the diagnosis of beriberi. We recommend surveillance, thiamine supplementation, and nutritional intervention.     

Rare and unusual histological variants of prostatic carcinoma: clinical significance

We review the clinicopathological features of the following unusual histological variants of prostatic carcinoma: small cell carcinoma, ductal adenocarcinoma, sarcomatoid (carcinosarcoma), basal cell, squamous cell and adenosquamous, and urothelial carcinoma. These variants are rare and account for 5-10% of carcinomas that originate in the prostate. Some develop from acinar adenocarcinoma after hormonal or radiation therapy. They are usually aggressive tumours that often present with secondary deposits. The outcome is generally poor. Only basal cell carcinoma is seen as a low-grade carcinoma.     

Low prevalence of Chlamydia psittaci in ocular adnexal lymphomas from Cuban patients

Most ocular adnexal lymphomas (OAL) are extranodal marginal zone B-cell lymphomas (EMZL) of mucosa-associated lymphoid tissue (MALT)-type. Chronic antigen stimulation has been suggested to have a pathogenetic role in EMZL and Chlamydia psittaci chronic infection has been recently associated with the development of OAL in a series of patients from Italy. To assess this association, an evaluation of the presence of C. psittaci was made in a different OAL population. DNA samples were obtained from formalin-fixed, paraffin-embedded sections samples of 26 patients with OAL, 20 non-OAL and 20 benign ocular lesions, diagnosed and treated between 1998 and 2003 at National Institute of Oncology in Havana, Cuba. All samples were histologically reviewed by an expert pathologist. Fluorescence in situ hybrization (FISH) analysis of translocations involving MALT1 was performed. The presence of bacterial DNA was assessed with a multiplex touchdown enzyme time release polymerase chain reaction. DNA sequencing was performed to confirm suspicious bands. Seventy-three percent of the OAL cases were EMZL and 81% were in stage IE. FISH analysis was performed in 13 OAL cases and none of them evidenced MALT1 translocations. DNA of C. psittaci was detected in 11% of the 46 lymphomas: two orbital EMZL and three non-OAL. All 20 benign ocular lesions were negative for C. psittaci. The low prevalence of C. psittaci in OAL suggests geographical differences in the etiology of this entity. International studies are needed to clarify the role of C. psittaci in OALs.