Microglial Piezo1 mechanosensitive channel as a therapeutic target in Alzheimer's disease.

Microglia are the resident macrophages of the central nervous system (CNS) that control brain development, maintain neural environments, respond to injuries, and regulate neuroinflammation. Despite their significant impact on various physiological and pathological processes across mammalian biology, there remains a notable gap in our understanding of how microglia perceive and transmit mechanical signals in both normal and diseased states. Recent studies have revealed that microglia possess the ability to detect changes in the mechanical properties of their environment, such as alterations in stiffness or pressure. These changes may occur during development, aging, or in pathological conditions such as trauma or neurodegenerative diseases. This review will discuss microglial Piezo1 mechanosensitive channels as potential therapeutic targets for Alzheimer's disease (AD). The structure, function, and modulation of Piezo1 will be discussed, as well as its role in facilitating microglial clearance of misfolded amyloid-ß (Aß) proteins implicated in the pathology of AD.

Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice.

A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimer's disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30°C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30°C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-ß (Aß)42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy with potential nonpharmacological management for some individuals with AD, and provides further evidence for the necessity of adopting personalized patient care.

Decreased MEFV gene expression in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and an autoimmune disease of unknown etiology in which the inflammatory pathology involves T cell activation. Genetic mutations in the Mediterranean fever (MEFV) gene, encoding pyrin, influence the severity of RA, but the underlying mechanisms are not completely understood. In this study, we investigated whether the full-length MEFV gene (MEFV-fl) and the exon 2-deleted splice isoform (MEFV-d2) expression are associated with or responsible for the clinical conditions of RA. This study include 47 patients with RA and 47 age- and gender-matched healthy controls. Quantitative real-time polymerase chain reaction analysis was performed to examine transcriptional changes in MEFV gene expression from peripheral blood samples. Reverse transcription-polymerase chain reaction of peripheral blood cells revealed the downregulation of MEFV-fl mRNA in non-treated patients compared with healthy controls and treated patients. MEFV-d2 expression was not different between groups. This is the first study to investigate the expression of MEFV transcript in RA. Deregulation of the MEFV gene is likely to result in uncontrolled inflammation as observed in RA. Therefore, downregulation of MEFV-fl may be involved in the pathogenesis of early-stage RA and treatment and may ameliorate MEFV-fl expression.

Surgical treatment of 32 cases of long-term atopic keratoconjunctivitis using the amniotic membrane.

PURPOSE: To evaluate the use of surgical treatment with amniotic membrane for long-term atopic keratoconjunctivitis. Damaged corneas were repaired with various techniques: amniotic membrane transplantations, amniotic membrane coverings, amniotic membrane fillings (AMFs), and amniotic membrane inlay fillings, the latter of which were combined with glycerol-preserved corneal transplants. METHODS: This retrospective study was conducted on 37 eyes belonging to 37 patients with atopic keratoconjunctivitis. Thirty-two patients were classified into four groups according to surgical technique. Five patients undergoing medical management served as controls. Surgical outcome was measured by recovery time and long-term visual improvement. RESULTS: In all surgical eyes, integrity of ocular tissues was effectively restored and symptoms were reduced at 24.4 ± 13 days post recovery. Mean best-corrected visual acuity improved from 0.6 ± 0.2 to 0.198 ± 0.16 logarithm of the minimum angle of resolution (P<0.001). There were no intraoperative or postoperative complications, with the exception of two recurring cases, both controlled by medication. Recovery time of the control groups lasted 52 ± 16 days. In controls, mean best-corrected visual acuity improved from 0.74 ± 0.15 to 0.54 ± 0.29 logarithm of the minimum angle of resolution (P ≤ 0.05). The vision improvement has significant difference for surgical treatment vs medical. (Mann-Whitney U-test, U = 119, P < 0.05, one tailed).Vision improvements remained stable during a mean follow-up period of 21.7 ± 3.8 months. CONCLUSION: Patients suffering from severe chronic atopic keratoconjunctivitis and its complications can benefit from suitable surgical treatments: transplants, covers, fillings, or corneal graft surgeries supplemented with AMFs.

The analgesic and antiemetic efficacy of gabapentin or ergotamine/caffeine for the treatment of postdural puncture headache.

PURPOSE: We investigated the analgesic and antiemetic efficacy of gabapentin or ergotamine/caffeine (Cafergot), in addition to conservative treatment consisting of bed rest and adequate fluid intake, for the treatment of postdural puncture headache (PDPH). METHODS: In this randomized, prospective, controlled study, gabapentin or Cafergot was administered to 42 adult patients suffering from PDPH. Patients were asked to record the severity of their headache and the number of vomiting episodes on a visual analogue scale (VAS) on days 1, 2, 3 and 4. The pain scale consisted of a 10 cm horizontal line marked from 0 (denoting no pain) to 10 (denoting worst possible imaginable pain) Emesis was scored as 0 = no emetic symptoms, 1 = nausea or 2 = vomiting. RESULTS: Demographic and anesthetic variables were similar between the groups. Gabapentin group had less pain, nausea and vomiting compared to the Cafergot group. No patients withdrew, gabapentin and Cafergot were well tolerated, and adverse events (somnolence, dizziness, tremor, and ataxia) did not occur. CONCLUSIONS: Gabapentin significantly reduced pain, nausea and vomiting compared to Cafergot in patients with PDPH. Lastly, we hypothesize that the gabaergic action of gabapentin, perhaps combined with other mechanisms, such as calcium channel blockade, may be responsible for its remarkable effects on PDPH.

Investigating paraoxonase-1 gene Q192R and L55M polymorphism in patients with renal cell cancer.

Increased oxidative stress can help promote carcinogenesis, including development of renal cell carcinoma. The enzyme protects low-density lipoproteins from oxidation and can be a factor in this process. PON1 Q192R and L55M paraoxonase gene polymorphisms were assessed in 60 renal cell carcinoma patients and 60 healthy controls. Genotypes were examined by PCR; the restriction enzyme AlwI was used to examine the Q192R polymorphism and Hsp92II for the L55M polymorphism. Significant differences in the PON1 Q192R polymorphism were found between patients and controls. The Q allele was more frequent in the patient group than in controls, while the R allele was more frequent in the control group. No significant differences were found in the L55M polymorphism. Additionally, there were no significant differences in L and M allele frequencies. We conclude that the R allele may protect against renal cell carcinoma.

Mediterranean fever gene mutation analysis in infertile Turkish males.

Male infertility is a common barrier that prevents successful conception. There have been reports of azoospermia in men with familial Mediterranean fever, some of whom had not been treated with colchicine. Variation in this disorder could be a risk factor for amyloidosis associated with azoospermia. We determined the frequency of 6 of the most common Mediterranean fever gene mutations, M680I, M694V, M694I, V726A, P369S, and A744S, in 74 infertile men, 155 men diagnosed with familial Mediterranean fever and 55 healthy fertile men in eastern Turkey. All three groups were screened for the 6 mutations using an amplification refractory mutation system and restriction fragment length polymorphism methods. Allelic frequencies were 2.7% for M694V and 1.35% for V726A in the infertile patient group and 1.8% for M694V and 1.8% for V726A in healthy subjects. Other mutations were not detected in patients or controls. The mutation frequency was not found to be significantly higher in infertile patients when compared with healthy fertile male controls. To our knowledge, this is the first study to determine the frequency of Mediterranean fever gene mutations in infertile male and the infertility rate of male patients with familial Mediterranean fever.

Which procedure should be chosen as a salvage operation in anterior hypospadias cases, meatal-based or onlay island flap? A comparative analysis.

We compared the outcome of flip-flap procedure (Mathieu procedure) with onlay island urethroplasty after previously failed repairs in anterior hypospadias cases. Charts of patients who underwent salvage flip-flap ( n=58) and onlay procedure ( n=24) were reviewed. Age range was 3-19 years (mean: 9+/-4.1) and 2-30 years (10.3+/-5.2) in the onlay and Mathieu groups, respectively ( p>0.05). In the onlay group, the flap was prepared from penile skin and preputial tissue in 5 and 19 cases, respectively. The meatal-based flap was laterally directed in 7 cases in the Mathieu group. The mean number of prior operations was greater in the onlay group when compared with the Mathieu group (1.85+/-1.53 vs. 1.41+/-0.65, respectively) although the difference was not statistically significant (Student's- t test, p>0.05). A total of 14 out of 58 (24.1%) and 6 out of 24 (25%) cases resulted in fistula formation in the Mathieu and island flap groups, respectively. Comparison of the rates of fistula formation did not reach statistical significance (Pearson chi(2), p=0.934). Skin dehiscence in one case and burying of the penis in another patient due to inadequacy of skin for coverage, occurred as complications in the onlay group. Splitting of the glans in 1, dehiscence of skin in 1 patient and complete breakdown of the neourethra in 1 case were the complications encountered in the Mathieu group. Both Mathieu and onlay island procedures have similar success rates as a salvage operation in anterior hypospadias cases if proper patient selection is done. The onlay procedure has been more commonly performed after a failed Mathieu procedure and the reverse rarely occurs.

Calyceal fornix rupture during cystography.

We report the first case of calyceal fornix rupture due to cystography in the literature. We recommend that instillation of all the contrast material should be attentively traced by the fluoroscope during cystography.

Outcome of pull-in procedure in children with severe post-disruption posterior urethral strictures.

A total of 17 children aged 5 to 15 years with the diagnosis of posttraumatic posterior urethral stricture were operated upon using a pull-in procedure during the last 9 years. Among the diagnostic tools, synchronous inspection of both the anterior and posterior urethra by cystoscopy yielded the most valuable information. A success rate of 70% was achieved with the procedure plus postoperative re-catheterization. A pedunculated tube prepared from the scrotal skin cured 2 patients after a series of failed operations. Difficult voiding occurring after removal of the stent due to an inappropriate pressure gradient created between the bladder neck and urethra usually benefits from short-term catheterization. Mild chordee was present in 1 patient. Ejaculation and erection were present in 3 children who reached puberty.

Objective penile vascular response to intraurethral prostaglandin E2 (dinoprostone).

PURPOSE: Intraurethral prostaglandin E2 (PGE2) administration is a noninvasive treatment modality for erectile dysfunction. The purpose of this study was to evaluate the objective effects of this agent by measuring peak systolic velocities of cavernosal arteries after intraurethral PGE2 administration and comparing with the results obtained with an intraurethral placebo gel and intracavernous papaverine injection. MATERIALS AND METHODS: The study group consisted of 22 consecutive impotent volunteers with a mean age of 46 years who had normal penile arterial responses as determined by penile arterial responses on papaverine-stimulated penile duplex ultrasonography. The peak systolic velocity in cavernosal arteries was recorded after intracavernous injection of 60 mg of papaverine. All patients received 1 mg of intraurethral PGE2 gel and placebo at 15-day intervals. The peak systolic velocities were recorded after each treatment. RESULTS: Mean peak systolic velocity achieved by intraurethral administration of PGE2 gel (25 +/- 8 cm/s) was less than that achieved by intracavernous papaverine (40 +/- 6 cm/s) but higher than that obtained by placebo (15 +/- 4 cm/s). Twelve patients had erections, while 9 had partial and 1 had no erection with intraurethral PGE2. Placebo did not cause any erections. No serious side effects were observed. CONCLUSION: Intraurethral administration of PGE2 appears to be an effective and simple method for increasing penile arterial flow and can be used during penile Doppler ultrasonography to stimulate the penile arterial system.

Synthesis and antidepressant activities of some 3,5-diphenyl-2-pyrazolines.

Ten new 3,5-diphenyl-2-pyrazoline derivatives were synthesised by reacting 1,3-diphenyl-2-propen-1-one with hydrazine hydrate. The chemical structures of the compounds were proved by means of their IR, 1H-NMR spectroscopic data and microanalyses. The antidepressant activities of these compounds were evaluated by the 'Porsolt Behavioural Despair Test' on Swiss-Webster mice. 3-(4-Methoxyphenyl)-5-(3,4-dimethoxyphenyl)-2-pyrazoline, 3-(4-methoxyphenyl)-5-(2-chloro-3,4-dimethoxyphenyl)-2-pyrazoline and 3-(4-chlorophenyl)-5-(2-chloro-3,4-dimethoxyphenyl)-2-pyrazoline reduced 41.94-48.62% immobility times at 100 mgkg(-1) dose level. In addition, it was found that 4-methoxy and 4-chloro substituents on the phenyl ring at position 3 of the pyrazoline ring increased the antidepressant activity; the replacement of these groups by bromo and methyl substituents decreased activity in mice.

Combination of transcutaneous electrical nerve stimulation and ondansetron in preventing cisplatin-induced emesis.

OBJECTIVE: To find out whether the combination of transcutaneous electrical nerve stimulation (TENS) and ondansetron had an increased antiemetic effect. MATERIALS AND METHODS: Fourteen testis and 11 bladder cancer patients were scheduled for 4 cycles of bleomycin-etoposide-cisplatin (BEP) or methotrexate-vinblastine-etoposide-cisplatin (MVEC) combination chemotherapy, respectively. At each cycle the whole cisplatin dose was given in 1 day that is 100 mg/m(2)/day in the BEP and 70 mg/m(2)/day in the MVEC protocols. Ondansetron was given at a dose of 12 mg/day and TENS was applied by commercially available 'Relief Band'(Maven Labs, Inc., Citrus Heights, Calif., USA). The first 3 cycles of each case were blindly randomized to one of the following regimens; TENS vs. ondansetron vs. a combination of both. The regimens were applied during the administration of cisplatin and the patients were asked to report their nausea according to a scale between 0 to 10. Also for each regimen the number of emetic attacks experienced during the administration of cisplatin was recorded by the same observer. Then the scores of each regimen were compared. RESULTS: The mean nausea scores for regimens TENS, ondansetron and TENS + ondansetron were found to be 5.12 +/- 2.54, 3.0 +/- 1.71 and 0.8 +/- 0.96, respectively. Ondansetron was better than TENS in preventing nausea (p = 0.000). However the combination of TENS and ondansetron resulted in a significant decrease in nausea scores when compared to TENS alone (p = 0.000) or ondansetron alone (p = 0.000). The mean number of emetic attacks for the TENS, ondansetron and TENS + ondansetron regimens were 3.16 +/- 1.84, 1.64 +/- 1.44 and 0.56 +/- 0.82, respectively. A statistically significant difference was present between the number of emetic attacks observed with the TENS + ondansetron combination and TENS alone (p = 0.000) or ondansetron alone (p = 0.001). Ondansetron was again better than TENS in preventing emetic attacks (p = 0.001). CONCLUSION: The use of TENS as an adjunct to ondansetron therapy has provided significant benefit in preventing nausea and emetic attacks caused by cisplatin.

Retrovesical echinococcal cyst causing renal failure and nocturnal enuresis in a child.

Although retrovesical hydatid cysts are observed in adulthood albeit very rarely, to our knowledge there is no case reported in childhood. In the current case, a huge retrovesical hydatid cyst caused obstructive uropathy, polydipsia, and secondary nocturnal enuresis in a child. Because the retrovesical hydatid cyst was firmly adherent to the neighboring structures, partial cystectomy could be performed. Perioperative and postoperative complications did not occur, and the symptoms relieved in the early postoperative period.

A rare cause of cystic testicular mass in an infant--cystic dysplasia of the testis.

In this article, a 6-month-old infant with cystic dysplasia of the testis (CDT) is presented. Although different genitourinary abnormalities associated with CDT have been reported, this is the first case of the association of CDT with penoscrotal hypospadias, unilateral undescended testicle, bilateral scrotal hernia, small and hypocompliant bladder and urethral obstruction. Orchiectomy was carried out for the treatment of this rare cause of testicular cystic mass.

Synthesis of 4(1H)-pyridinone derivatives and investigation of analgesic and antiinflammatory activities.

This paper describes recent results of a research program aimed at the synthesis and pharmacological evaluation of new 4(1H)-pyridinone derivatives belonging to the 1,3-disubstituted series (4-11). These compounds were structurally planned by applying the molecular hybridization strategy on previously described 1,2-disubstituted-4(1H)-pyridinone derivatives, considered as lead compounds, which present potent analgesic properties (M.D. Aytemir, T. Uzbay, D.D. Erol, Arzneim. Forsch. (Drug Res.) 49 (1999) 250). Their chemical structures have been proved by means of their IR and 1H NMR data and by elemental analysis. The analgesic profile of the title compounds (4-11), evaluated by the model of abdominal constrictions induced by acetic acid, showed that all the 4(1H)-pyridinone derivatives were active, exhibiting an analgesic activity comparable with that of aspirin (acetyl salicylic acid) used as a standard. The antiinflammatory profile of the synthesized compounds, evaluated by the model of carrageenan rat paw edema, showed that all compounds were active and were comparable with indomethacin used as a standard.

The application of appendiceal Mitrofanoff principle to Stanford pouch.

OBJECTIVE: The present paper reports the functional aspects of a novel continent cutaneous reservoir. PATIENTS AND METHODS: A continent cutaneous reservoir was constructed by the application of appendiceal Mitrofanoff principle to Stanford pouch in four male and three female patients between 1995-1998 in our clinic. The mean age of the patients was 45.6 years (7-67 years) and the etiological factor was carcinoma of the bladder in four, interstitial cystitis in one and extrophy-epispadias complex in two cases. Patients were followed with arterial blood gas determination, serum biochemistry, urinalysis and urine culture at postoperative 3 weeks and by 3-month intervals thereafter. Additionally, pouch graphy, abdominal ultrasonography and urodynamic tests were performed every 6 months. RESULTS: After the operation all the patients were continent. Stoma was transferred from the umbilicus to the right lower quadrant in one case (14.3%) because of difficulty in catheterisation. Pouch graphy at postoperative 6 months revealed low-grade vesicoureteral reflux in two (28.6%) patients and one (14.3%) of them required suppressive antibiotic therapy because of pyelonephritis episodes. Another patient developed hyperchloremic metabolic acidosis and needed oral alkaline supplementation. The mean pouch capacity measured at postoperative 6 months was 423 (350-550) ml and the mean end-filling pressure was found as 21 (18-25) cmH2O. After a mean follow-up period of 37 (18-45) months all the patients remained continent and stable. CONCLUSION: The continent cutaneous reservoir presented herein is our alternative to orthotopic neobladder in female patients undergoing radical cystectomy. It also provided continence as well as good quality of life in patients with extrophy-epispadias complex and male patients after radical cystectomy and urethrectomy.

Sertoli cell tumor in a prepubertal boy mimicking testicular torsion.

A 9-year-old boy presented with left, intermittent testicular pain that was present for 3 days. On physical examination, left testis was grossly enlarged and firm but mildly tender. Serum alpha-fetoprotein and beta-human chorionic gonadotropin levels were within normal range. Color doppler ultrasonography which was performed to rule out testicular torsion revealed an intratesticular mass located at the upper pole of left testis and left radical orchiectomy was performed. The histopathological diagnosis was Sertoli cell tumor.

An unusual cause of urinary retention: a primary retrovesical echinococcal cyst.

We present a patient with symptoms of frequency, a mild decrease in urinary stream, and urinary retention due to a huge hydatid cyst located in the retrovesical region. Chest radiography and abdominal computed tomography did not reveal any other site of hydatid disease involvement. Since the cyst was in intimate contact with the seminal vesicles and the vasa deferentia, part of the hydatid sac wall adherent to these structures was left behind during the surgical excision. The patient was free of voiding symptoms, and no other episode of urinary retention had occurred at 6 months of follow-up. Pelvic computed tomography did not reveal recurrence of hydatid disease at 6 months postoperatively.